Does atrial fibrillation cause cognitive decline and dementia?

Does atrial fibrillation cause cognitive decline and dementia? Abstract Atrial fibrillation (AF) and dementia are both frequent diseases with substantial socioeconomic impact. While AF has been associated with cognitive dysfunction and dementia, we currently lack an exact understanding of the complex association between AF and cognitive decline. Based on an extended literature search we summarize key publications focusing on AF-related cognitive decline and dementia. Moreover, ongoing trials and potential therapeutic implications are discussed. While further prospective studies using a standardized definition of AF and cognitive decline are urgently needed, growing evidence supports the hypothesis that AF is an independent risk factor for cognitive decline and dementia in general and for Alzheimer’s disease in particular. In addition to AF-related ischaemic stroke, white matter damage and systemic inflammation are candidate pathomechanisms and therefore a potential target for prevention of cognitive decline. Whether individualized best-medical therapy of AF holds the promise of preventing cognitive decline should be tested in randomized trials. Atrial fibrillation , Dementia , Alzheimer’s disease , Cognitive decline Introduction It is widely accepted that cerebral health is linked to cardiac health in many ways.1,2 Atrial fibrillation (AF) as well as dementia are frequent diseases, predominantly affecting the elderly. So far, AF is not regarded as independent predictor for dementia, despite of epidemiological similarities and shared (cardiovascular) risk factors. A better understanding of the AF-related risk for dementia might help to tackle these worldwide health problems. This narrative review is based on a literature research in PubMed.gov–last done in May 2016—using the keyword ‘atrial fibrillation’ in various combinations with ‘cognition’, ‘neurocognitive’, ‘cognitive performance/dysfunction/impairment/decline’, ‘Alzheimer’s’ and ‘dementia’ as well as ‘pathophysiology’ and ‘pathomechanism’ with the purpose to outline current knowledge on the relationship of AF and dementia and provide a résumé of explanatory research on the underlying pathomechanisms. Epidemiology of atrial fibrillation and dementia Both AF as well as dementia are frequent diseases—especially in the elderly. Moreover, both are expected to be among the most prominent global epidemiological trends of the 21st century with an overwhelming burden on worldwide health care systems. The number of patients with dementia seems to stabilize in European countries despite population ageing.3 However, the estimated prevalence rates remain substantial in Western Europe: 2600 per 100 000 for those aged 65 years and older, while up to 21 700 per 100 000 for those aged 85 years and above. Women have a 1.5-fold higher life-time risk of developing Alzheimer’s dementia.4 The estimated prevalence rates for AF range from 3700 to 4700 per 100 000 in those aged 60–70 years and from 10 000 to 17 000 per 100 000 for those aged 80 years and older according to a recent review of European data.5 In addition, AF is more prevalent in men, who have a 1.2-fold greater risk of developing AF than women after adjustment for age and predisposing conditions.5 According to the Rotterdam study, the lifetime risk of developing AF by the age of 55 years is 24% in men and 22% in women.6 Given a prevalence of dementia of 2.6% and AF of 3.7%, in theory 6.2% of individuals will be suffering from either one or both diseases, assuming independence of these two conditions. Methodological difficulties in establishing an association of AF with dementia The wide variety of terms used to describe cognitive dysfunction or dementia in clinical studies evaluating the association of AF and dementia renders the interpretation difficult. Terms include: ‘cognitive decline’, ‘cognitive impairment’, ‘low cognitive function’, ‘low cognitive performance’, ‘memory impairment’, ‘visuospatial memory loss’, ‘incident dementia’, ‘dementia without specification’, ‘Alzheimer’s dementia’, and ‘vascular dementia’ amongst others. In addition, a large variety of neuropsychological test batteries is used and often describes cognitive dysfunction in very specific domains. Moreover, accurate diagnosis of dementia is often delayed since the early symptoms often go unnoticed or may be trivialised. Consequently, adequate tools are not used for the diagnosis, likely resulting in insufficient screening for dementia and under-diagnosis in primary care.7 In addition, there is substantial heterogeneity in the diagnosis of dementia according to the commonly used classification schemes (DSM-II, DSM-III-R, DSM-IV, ICD-9 or CAMDEX). In fact, the prevalence of ‘dementia’ in a defined population-based cohort varied from 3.1 to 29.1% merely depending on which definition was used.8 Applying ICD-10 or DSM-IV criteria to the general population will result in 3.1% vs. 9.6% cases of dementia, respectively.9 These apparent discrepancies in diagnostic rates have been described for further diagnostic criteria, i.e. such as proposed by the National Institute on Aging and the Alzheimer’s Association (NIA-AA) or the International Working Group for New Research Criteria for the Diagnosis of Alzheimer’s Disease (IWG).10 Similar difficulties also apply for detection and definition of AF, despite of the fact that ECG-based diagnosis is rather straightforward. About two thirds of AF patients suffer from palpitations, fatigue, dyspnoea or dizziness—so called ‘symptomatic’ AF.11 However, given the often asymptomatic and intermittent nature of AF, the diagnosis of AF is frequently delayed. As an example, a population-based screening among 13 331 individuals aged 75 and 76 years in Sweden detected previously unknown (and therefore untreated) AF in 3% of these individuals using intermittent ECG recordings over 2 weeks.12 Moreover, the definition of AF (i.e. ‘any arrhythmia that has the ECG characteristics of AF and lasts sufficiently long for a 12-lead ECG to be recorded, or at least 30 s on a rhythm strip’ according to Camm et al., (ESC guidelines 2010)13 is based on expert consensus only, namely the ACC/AHA/ESC 2006 guidelines.14 Notably, adaptations of that definition as well as technical advances such as intracardiac monitoring devices or loop recorders resulted in lower (≥ 5 s) or higher bounds (e.g. ≥ 2 min, ≥ 2.5 min, or even 6 min etc.).15 So far, the optimal duration and most cost-effective method of AF detection is a matter of debate, and guideline recommendations remain vague, especially for stroke patients.16–18 Both atrial fibrillation and dementia share the same risk factors Studies evaluating a causal relationship of AF and dementia have to account for overlapping risk factors. Various conditions such as old age, diabetes, chronic kidney disease, sleep apnea, hypertension, heart failure, heavy alcohol consumption, and coronary heart disease are associated with AF as well as dementia,19–31 for further details see Table 1. Table 1 Risk factors associated with atrial fibrillation (AF) as well as dementia or cognitive decline Condition  Author (Enrollment)  Cohort and study design  Cohort characteristics  Methods  Main findings  Diabetes mellitus and dementia  Arvanitakis et al., 200419 (1994–2003)  Catholic nuns, priests, and brothers underwent detailed clinical evaluation. Longitudinal cohort study, United States  n = 824  NINDS- ADRDA Episodic, semantic, working memory, perceptual speed & visuospatial abilities.  Patients with diabetes mellitus had a 65% increase in the risk of developing Alzheimeŕs compared to those without diabetes: HR 1.65 (95% CI 1.10–2.47) after adjusting for age, sex, and educational level.  age 74.4 ± 6.1 (DM) & 75.2 ± 75 (no DM) years, male 44.9% (DM) vs. 28.7% (no DM) follow-up 5.5 years  Diabetes mellitus and AF  Iguchi et al., 200820 (2006)  Non-employed inhabitants of Kurashiki- City, aged >40 years. Community based study, Japan  n = 41 436  ECG  DM was associated with AF in men: OR 1.50 (95% CI 1.15–1.95) and in women: OR 1.40 (95% CI 1.04–1.89) after adjusting for sex, diabetes mellitus, hypercholesterolemia, cardiac disease, chronic kidney disease.  age 76.6 ± 8.5 (AF) years & 71.4 ± 10.5 (no AF) male 50% (AF) & 33% (no AF), no follow-up  Chronic kidney disease and dementia  Hailpern et al., 200721 (1988–1994)  Civilian, noninstitutionalized adults >18 years from the NHANES III Study. Cross-sectional population based study, United States  n = 4849  SDLT, DSST, SRTT  CKD was significantly associated with poor visual attention and learning/concentration OR 2.41 (95% CI 1.30–5.63). Analysis adjusted for age, gender, race, diabetes, and other known potential confounders.  median age 36 years, 49% male, Afro-American 11%, follow-up n.a.  Chronic kidney disease and AF  Liao et al., 201522 (1996–2011)  Patients undergoing renal replacement therapy were compared to patients without CKD or CKD without renal replacement therapy. Retrospective analysis, Taiwan  n = 134 901  ICD-9  Patients with end stage renal disease had a significantly higher risk of new-onset AF: HR 1.28 (95% CI 1.22–1.34) adjusted for age, gender, hypertension, DM, HF, CAD, PAOD, cerebral vascular accident, COPD, cancer & liver cirrhosis.  age 61.7 ± 14.3 years, 49.5% male follow-up 5.1 ± 4.1 years  Sleep apnea and dementia  Spira et al., 200823 (1986–1988)  Community dwelling women aged ≥65 years, Study of Osteoporotic Fractures. Prospective observational study, United States  n = 448  MMSE, Trails B, PSG  All sleep disorder indices were associated with cognitive impairment according to MMSE: OR 3.4 (95% CI 1.4–8.1), adjusted for age, education, and SSRI use.  age 82.8 ± 3.4 years, male 0%, Caucasian 91.5% follow-up 16 years  Sleep apnea and AF  Gami et al. 200724 (1987–2003)  Adult residents of Olmsted county, 1st polysomnography. Retro-spective cohort study, United States  n = 3542  PSG, ECG  Decrease in nocturnal oxygen saturation was a predictor for AF for subjects < 65 years: HR 3.29 (95% CI 1.35–8.04) adjusted for age, male gender, CAD, BMI, nocturnal oxygen saturation.  age 49 ± 14 years, male 66%, follow-up 15 years  Hypertension and cognitive dysfunction  Böhm et al., 201525 (2001–2004)  Patients ≥55 years without heart failure but CAD, PAOD, TIA/stroke or diabetes & organ damage. Data from ONTARGET & TRANSCEND.  n = 24 593  MMSE  SBP-CV (OR1.32 (95% CI 1.10–1.58)) and mean heart rate (OR 1.40 (95% CI 1.18–1.66)) were associated with cognitive decline after adjusting for a large variety of factors (incl. MMST baseline).  mean age 66 years, male 72.5%, Caucasian 74%, follow up 56 months  Hypertension and AF  Tremblay-Gravel et al., 201526 (1999–2008)  Patients ≥65 years or LVEF ≤35% or NYHA class II–IV symptoms. Pooled data from AFFIRM & AF-CHF.  n = 2715  ECG  AF recurrence after cardioversion was higher in patients with SBP with >140 mmHg. HR 1.47 (95% CI 1.12–1.93) adjusted for BMI, AF duration, rhythm at baseline, left atrial dimension, anticoagulant use, calcium channel blocker use.  mean age 68 ± 8 years, male 66%, follow up 3.5 years  Heart failure and dementia  Qiu et al., 200627 (1987)  All registered inhabitants of Kungsholmen district of Stockholm, ≥ 75years. Community-based cohort study, Sweden  n = 1301  DSM-III, MMSE  Heart failure is associated with dementia and Alzheimer disease: HR 1.84 (95% CI 1.35–2.51) adjusted for age, sex, education, baseline MMSE, stroke, diabetes mellitus, antihypertensives, blood pressure, pulse, BMI, and survival status.  age 83.3 ± 5.4 (HF) & 81.2 ± 4.8 (non HF), male 20% (HF) & 23.9% (non HF), follow-up 5 years  Heart failure or coronary heart disease and AF  Benjamin et al., 199428 (1948)  Cohort of the Framingham study, subjects restricted 55–94 years. Population-based estimates, United States  n = 4731  ECG  HF associated with risk of AF in men: OR 4.5 (95% CI 3.1–6.6) & women: OR 5.9 (95% CI 4.2–8.4); CHD associated with AF in men: 1.4 (95% CI 1.0–2.0) & women: 1.2 (95% CI 0.8–1.8) adjusted for age, diabetes, HT, valvular heart disease.  mean age women 75 & men 72%; male 44% follow-up 38 years  Coronary heart disease and cognitive impairment  Roberts et al., 201029 (2004)  Incidence of amnestic and non-amnestic mild cognitive impairment in Olmsted County. Population-based longitudinal cohort study, United States  n = 1969  Dementia Rating Scale, testing of memory, executive function, language, visuospatial skills.  CHD associated with mild cognitive impairment: OR 1.85 (95% CI 1.12–3.05) but not with amnestic. Analysis adjusted for age, sex, education, DM, HT, stroke, BMI, depression, dyslipidaemia, ApoE genotype.  mean age 80.4 years, male 50.9%, Caucasian 98%, follow-up n.a.  Heavy alcohol consumption and dementia  Mukamal et al., 200330 (1989–1993)  Cardiovascular Health Study aged ≥65years, independent, randomly selected from Medicare. Population-based cohort study, United States  n = 5888  DSM-IV, 3MSE, MMSE, modified MMSE and MRI, DSST, IQCODE  Heavy alcohol consumption associated with dementia: OR 1.22 (95% CI 0.60–2.49) adjusted for age, sex, race, ApoE4, education, income, oestrogen replacement therapy, smoking, diabetes, BMI, cholesterol, AF, CHF, stroke/TIA.  mean age 78 years, male ∼41%, Afro-American ∼10%, follow-up 6 years  Heavy alcohol consumption and AF  Mukamal et al., 200531 (1976, 1981)  Randomly chosen participants from the Copenhagen Population Register. Population-based cohort study, Denmark  n = 16 415  ECG  Heavy alcohol consumption associated with AF: HR 1.45 (95% CI 1.02–2.04) adjusted for age, smoking, education, cohabitation, history of CVD, diabetes, income, physical activity, BMI, height.  median age 55.8 (men) & 56.8 (women), male 46,%, follow-up 15 years  Condition  Author (Enrollment)  Cohort and study design  Cohort characteristics  Methods  Main findings  Diabetes mellitus and dementia  Arvanitakis et al., 200419 (1994–2003)  Catholic nuns, priests, and brothers underwent detailed clinical evaluation. Longitudinal cohort study, United States  n = 824  NINDS- ADRDA Episodic, semantic, working memory, perceptual speed & visuospatial abilities.  Patients with diabetes mellitus had a 65% increase in the risk of developing Alzheimeŕs compared to those without diabetes: HR 1.65 (95% CI 1.10–2.47) after adjusting for age, sex, and educational level.  age 74.4 ± 6.1 (DM) & 75.2 ± 75 (no DM) years, male 44.9% (DM) vs. 28.7% (no DM) follow-up 5.5 years  Diabetes mellitus and AF  Iguchi et al., 200820 (2006)  Non-employed inhabitants of Kurashiki- City, aged >40 years. Community based study, Japan  n = 41 436  ECG  DM was associated with AF in men: OR 1.50 (95% CI 1.15–1.95) and in women: OR 1.40 (95% CI 1.04–1.89) after adjusting for sex, diabetes mellitus, hypercholesterolemia, cardiac disease, chronic kidney disease.  age 76.6 ± 8.5 (AF) years & 71.4 ± 10.5 (no AF) male 50% (AF) & 33% (no AF), no follow-up  Chronic kidney disease and dementia  Hailpern et al., 200721 (1988–1994)  Civilian, noninstitutionalized adults >18 years from the NHANES III Study. Cross-sectional population based study, United States  n = 4849  SDLT, DSST, SRTT  CKD was significantly associated with poor visual attention and learning/concentration OR 2.41 (95% CI 1.30–5.63). Analysis adjusted for age, gender, race, diabetes, and other known potential confounders.  median age 36 years, 49% male, Afro-American 11%, follow-up n.a.  Chronic kidney disease and AF  Liao et al., 201522 (1996–2011)  Patients undergoing renal replacement therapy were compared to patients without CKD or CKD without renal replacement therapy. Retrospective analysis, Taiwan  n = 134 901  ICD-9  Patients with end stage renal disease had a significantly higher risk of new-onset AF: HR 1.28 (95% CI 1.22–1.34) adjusted for age, gender, hypertension, DM, HF, CAD, PAOD, cerebral vascular accident, COPD, cancer & liver cirrhosis.  age 61.7 ± 14.3 years, 49.5% male follow-up 5.1 ± 4.1 years  Sleep apnea and dementia  Spira et al., 200823 (1986–1988)  Community dwelling women aged ≥65 years, Study of Osteoporotic Fractures. Prospective observational study, United States  n = 448  MMSE, Trails B, PSG  All sleep disorder indices were associated with cognitive impairment according to MMSE: OR 3.4 (95% CI 1.4–8.1), adjusted for age, education, and SSRI use.  age 82.8 ± 3.4 years, male 0%, Caucasian 91.5% follow-up 16 years  Sleep apnea and AF  Gami et al. 200724 (1987–2003)  Adult residents of Olmsted county, 1st polysomnography. Retro-spective cohort study, United States  n = 3542  PSG, ECG  Decrease in nocturnal oxygen saturation was a predictor for AF for subjects < 65 years: HR 3.29 (95% CI 1.35–8.04) adjusted for age, male gender, CAD, BMI, nocturnal oxygen saturation.  age 49 ± 14 years, male 66%, follow-up 15 years  Hypertension and cognitive dysfunction  Böhm et al., 201525 (2001–2004)  Patients ≥55 years without heart failure but CAD, PAOD, TIA/stroke or diabetes & organ damage. Data from ONTARGET & TRANSCEND.  n = 24 593  MMSE  SBP-CV (OR1.32 (95% CI 1.10–1.58)) and mean heart rate (OR 1.40 (95% CI 1.18–1.66)) were associated with cognitive decline after adjusting for a large variety of factors (incl. MMST baseline).  mean age 66 years, male 72.5%, Caucasian 74%, follow up 56 months  Hypertension and AF  Tremblay-Gravel et al., 201526 (1999–2008)  Patients ≥65 years or LVEF ≤35% or NYHA class II–IV symptoms. Pooled data from AFFIRM & AF-CHF.  n = 2715  ECG  AF recurrence after cardioversion was higher in patients with SBP with >140 mmHg. HR 1.47 (95% CI 1.12–1.93) adjusted for BMI, AF duration, rhythm at baseline, left atrial dimension, anticoagulant use, calcium channel blocker use.  mean age 68 ± 8 years, male 66%, follow up 3.5 years  Heart failure and dementia  Qiu et al., 200627 (1987)  All registered inhabitants of Kungsholmen district of Stockholm, ≥ 75years. Community-based cohort study, Sweden  n = 1301  DSM-III, MMSE  Heart failure is associated with dementia and Alzheimer disease: HR 1.84 (95% CI 1.35–2.51) adjusted for age, sex, education, baseline MMSE, stroke, diabetes mellitus, antihypertensives, blood pressure, pulse, BMI, and survival status.  age 83.3 ± 5.4 (HF) & 81.2 ± 4.8 (non HF), male 20% (HF) & 23.9% (non HF), follow-up 5 years  Heart failure or coronary heart disease and AF  Benjamin et al., 199428 (1948)  Cohort of the Framingham study, subjects restricted 55–94 years. Population-based estimates, United States  n = 4731  ECG  HF associated with risk of AF in men: OR 4.5 (95% CI 3.1–6.6) & women: OR 5.9 (95% CI 4.2–8.4); CHD associated with AF in men: 1.4 (95% CI 1.0–2.0) & women: 1.2 (95% CI 0.8–1.8) adjusted for age, diabetes, HT, valvular heart disease.  mean age women 75 & men 72%; male 44% follow-up 38 years  Coronary heart disease and cognitive impairment  Roberts et al., 201029 (2004)  Incidence of amnestic and non-amnestic mild cognitive impairment in Olmsted County. Population-based longitudinal cohort study, United States  n = 1969  Dementia Rating Scale, testing of memory, executive function, language, visuospatial skills.  CHD associated with mild cognitive impairment: OR 1.85 (95% CI 1.12–3.05) but not with amnestic. Analysis adjusted for age, sex, education, DM, HT, stroke, BMI, depression, dyslipidaemia, ApoE genotype.  mean age 80.4 years, male 50.9%, Caucasian 98%, follow-up n.a.  Heavy alcohol consumption and dementia  Mukamal et al., 200330 (1989–1993)  Cardiovascular Health Study aged ≥65years, independent, randomly selected from Medicare. Population-based cohort study, United States  n = 5888  DSM-IV, 3MSE, MMSE, modified MMSE and MRI, DSST, IQCODE  Heavy alcohol consumption associated with dementia: OR 1.22 (95% CI 0.60–2.49) adjusted for age, sex, race, ApoE4, education, income, oestrogen replacement therapy, smoking, diabetes, BMI, cholesterol, AF, CHF, stroke/TIA.  mean age 78 years, male ∼41%, Afro-American ∼10%, follow-up 6 years  Heavy alcohol consumption and AF  Mukamal et al., 200531 (1976, 1981)  Randomly chosen participants from the Copenhagen Population Register. Population-based cohort study, Denmark  n = 16 415  ECG  Heavy alcohol consumption associated with AF: HR 1.45 (95% CI 1.02–2.04) adjusted for age, smoking, education, cohabitation, history of CVD, diabetes, income, physical activity, BMI, height.  median age 55.8 (men) & 56.8 (women), male 46,%, follow-up 15 years  NINDS-ADRDA, National Institute of Neurological Disorders and Stroke and Alzheimer’s disease and related disorders association; MMSE, Mini-Mental State Examination; SDLT, Serial Digit Learning Test; DSST, Digit Symbol Substitution Test, SRTT, Simple Reaction Time Test; Trails B, Trail Making Test Part B; IQCODE, Informant Questionnaire on the cognitive decline of the Elderly; PSG, Polysomnography; HTN, Hypertension; HF, heart failure; CAD, coronary artery disease; PAOD, peripheral arterial occlusive disease; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; SBP-CV, Systolic blood-pressure coefficient of variation; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; GFR, Glomerular Filtration Rate; BMI, Body Mass Index; SSRI, selective serotonin reuptake inhibitor; NHANES, National Health and Nutrition Examination Survey. AF is a risk factor for cognitive decline and dementia—candidate pathomechanisms A number of prospective studies demonstrated an association between AF and cognitive decline or dementia (Table 2;32–38). As an example, the combined post-hoc analysis of two prospective multicenter trials demonstrated that AF was associated with an increased risk of cognitive decline [HR 1.14 (95% CI 1.03–1.26)], dementia [HR 1.30 (95% CI 1.14–1.49)] as well as loss of independence in performing activities of daily living [HR 1.35 (95% CI 1.19–1.54)].36 The Cardiovascular Health Study reported a faster cognitive decline in patients who developed AF within the next 7 years.37 In addition, the prospective Intermountain Heart Collaborative Study demonstrated a significantly increased risk of dementia in AF patients [HR 1.36 (95% CI 1.1–1.6)].35 A similar association was found for AF and Alzheimer’s dementia (AD), and the relative risk (RR) was significantly higher in AF patients aged <70 years with no apparent association in older AF patients. However, a major limitation of these studies is missing serial brain imaging for covert strokes or white matter hyperintensities. Table 2 Studies assessing an association between atrial fibrillation (AF) and dementia or cognitive decline Author (Enrollment)  Cohort and study design  Cohort characteristics  Methods  Main findings  Ott et al., 199732 (1989)  Inhabitants of Rotterdam with dementia compared to subjects without dementia regarding the presence of AF. Population based prospective cohort study, Netherlands  n = 6584  AF: 12-lead ECG, Cognition: DSM-IIIR, MMSE, NINDS-ADRDA, NINDS-AIREN  Dementia was more than twice as common in subjects with AF without history of stroke (<75 years): OR 2.6 (95% CI 0.6–11.4) adjusted for age, sex, and stroke history.  age 69.2 ± 9.1 years, male 41.8%  Elias et al., 200633 (1971)  Men with a history of AF compared to men without AF. Community based sample, United States  n = 1011  AF: 12-lead ECG or Holter. Cognition: DSM-IV, NINDS-ADRDA, Wechsler scales, Trail-making A+B  AF in stroke-free men was associated with lower performance in global cognitive ability and cognitive abilities: HR 4.0 (95% CI 1.8- 8.7) adjusted for age, education, multiple cardiovascular risk factors, and cardiovascular disease.  age 60.5 ± 9.4 (noAF) & 68.1 ± 7.0 (AF), male 100% follow-up 30 years  Knecht et al., 200834 (2004–2007)  AF patients without stroke according to brain imaging compared to non-AF subjects. Cohort based -community controlled MRI study, Germany  n = 533  AF: 12-lead ECG. Cognition: STroop-Test, DSST, Trail A+B, digit span, Rey Osterrieth complex figure test  AF was independently related to lower hippocampal volume (p < 0.01), total brain volume (p < 0.01) and lower cognitive performance in learning and memory (ß=-0.115, SE 0.115, p < 0.01) and attention and executive functions (ß=0.105, SE -0.109, p < 0.01). Analysis adjusted for age, gender, education, systolic blood pressure, BMI, HT, diabetes, dyslipoproteinemia, smoking, CAD, medication.  age 64 ± 7 (noAF) & 60 ± 12 (AF); male 43.8% (no AF) & 83.8% (AF)  Bunch et al., 201035 (1994)  Patients diagnosed with any type of heart disease from the Intermountain Healthcare system. Prospective cohort study, United Sates  n = 10 161  AF: ICD-9 codes, ECG-database. Cognition: ICD-9  AF was an independent risk for dementia, all subtypes (senile, vascular, Alzheimeŕs and non-specified dementia) and faster cognitive decline. For Alzheimeŕs <70 years: OR 2.30 (p < 0.01) multivariable-adjusted age-based analysis.  age 60.6 ± 17.9 years, male 60%, white 89%, follow-up 5 years  Marzona et al., 201236 (2001–2004)  Patients aged >55 years with cardiovascular disease or diabetes an end-organ damage. Post-hoc analysis of ONTARGET & TRANSCEND.  n = 31 506  AF: 12-lead ECG. Cognition: MMSE  AF was associated with risk of dementia HR 1.30 (95% CI 1.14- 1.49) adjusted for age, education, sex, baseline MMSE, SBP, stroke/TIA, HT, diabetes, albuminuria, MI, creatinine, medication, smoking, BMI, physical activity, sleep apnea, alcohol consumption.  age 66.5 ± 7.2 years, male 71.3%, follow-up 56 months  Thacker et al., 201337 (1989–1993)  Cognition in AF patients compared to non-AF patients without prior stroke, aged >65 years. Community-based prospective study, United States  n = 5150  AF: 12-lead ECG, Cognition: 3MSE DSST  In the group of 75 year old subjects, compared to non-AF patients, AF patients showed faster cognitive decline in the absence of overt stroke with a decline of -3.0 points (95% CI -4.1- -1.8) in 3MSE scores over the following 5 years. Analysis adjusted for age, sex, race, education, cigarette smoking, alcohol use, diabetes, HT, blood pressure, CAD, HF, and the interaction of age.  mean age 73.0 ± 5.4 years, male 41.2% follow-up 7 years  deBrujin et al., 201538 (1989)  Association of AF with incident dementia in people > 55 years. Population based prospective cohort study, Netherlands  n = 6514  AF: 12-lead ECG, Cognition: 3MSE, GMSS, CAMDEX-R  Incident AF was associated with risk of dementia in participants <67 years: HR 1.81 (95% CI 1.11- 2.94) adjusted for age, sex, diabetes mellitus, smoking, total cholesterol and HDL, lipid-lowering medication, BP, BP lowering medication, educational level, ever use of oral anticoagulation, CAD, HF, ApoE4.  age 68.3 ± 8.5 (no AF) & 75.7 ± 8.1 (AF), male 41.6% (no AF) & 49.4% (AF), follow-up 20 years  Author (Enrollment)  Cohort and study design  Cohort characteristics  Methods  Main findings  Ott et al., 199732 (1989)  Inhabitants of Rotterdam with dementia compared to subjects without dementia regarding the presence of AF. Population based prospective cohort study, Netherlands  n = 6584  AF: 12-lead ECG, Cognition: DSM-IIIR, MMSE, NINDS-ADRDA, NINDS-AIREN  Dementia was more than twice as common in subjects with AF without history of stroke (<75 years): OR 2.6 (95% CI 0.6–11.4) adjusted for age, sex, and stroke history.  age 69.2 ± 9.1 years, male 41.8%  Elias et al., 200633 (1971)  Men with a history of AF compared to men without AF. Community based sample, United States  n = 1011  AF: 12-lead ECG or Holter. Cognition: DSM-IV, NINDS-ADRDA, Wechsler scales, Trail-making A+B  AF in stroke-free men was associated with lower performance in global cognitive ability and cognitive abilities: HR 4.0 (95% CI 1.8- 8.7) adjusted for age, education, multiple cardiovascular risk factors, and cardiovascular disease.  age 60.5 ± 9.4 (noAF) & 68.1 ± 7.0 (AF), male 100% follow-up 30 years  Knecht et al., 200834 (2004–2007)  AF patients without stroke according to brain imaging compared to non-AF subjects. Cohort based -community controlled MRI study, Germany  n = 533  AF: 12-lead ECG. Cognition: STroop-Test, DSST, Trail A+B, digit span, Rey Osterrieth complex figure test  AF was independently related to lower hippocampal volume (p < 0.01), total brain volume (p < 0.01) and lower cognitive performance in learning and memory (ß=-0.115, SE 0.115, p < 0.01) and attention and executive functions (ß=0.105, SE -0.109, p < 0.01). Analysis adjusted for age, gender, education, systolic blood pressure, BMI, HT, diabetes, dyslipoproteinemia, smoking, CAD, medication.  age 64 ± 7 (noAF) & 60 ± 12 (AF); male 43.8% (no AF) & 83.8% (AF)  Bunch et al., 201035 (1994)  Patients diagnosed with any type of heart disease from the Intermountain Healthcare system. Prospective cohort study, United Sates  n = 10 161  AF: ICD-9 codes, ECG-database. Cognition: ICD-9  AF was an independent risk for dementia, all subtypes (senile, vascular, Alzheimeŕs and non-specified dementia) and faster cognitive decline. For Alzheimeŕs <70 years: OR 2.30 (p < 0.01) multivariable-adjusted age-based analysis.  age 60.6 ± 17.9 years, male 60%, white 89%, follow-up 5 years  Marzona et al., 201236 (2001–2004)  Patients aged >55 years with cardiovascular disease or diabetes an end-organ damage. Post-hoc analysis of ONTARGET & TRANSCEND.  n = 31 506  AF: 12-lead ECG. Cognition: MMSE  AF was associated with risk of dementia HR 1.30 (95% CI 1.14- 1.49) adjusted for age, education, sex, baseline MMSE, SBP, stroke/TIA, HT, diabetes, albuminuria, MI, creatinine, medication, smoking, BMI, physical activity, sleep apnea, alcohol consumption.  age 66.5 ± 7.2 years, male 71.3%, follow-up 56 months  Thacker et al., 201337 (1989–1993)  Cognition in AF patients compared to non-AF patients without prior stroke, aged >65 years. Community-based prospective study, United States  n = 5150  AF: 12-lead ECG, Cognition: 3MSE DSST  In the group of 75 year old subjects, compared to non-AF patients, AF patients showed faster cognitive decline in the absence of overt stroke with a decline of -3.0 points (95% CI -4.1- -1.8) in 3MSE scores over the following 5 years. Analysis adjusted for age, sex, race, education, cigarette smoking, alcohol use, diabetes, HT, blood pressure, CAD, HF, and the interaction of age.  mean age 73.0 ± 5.4 years, male 41.2% follow-up 7 years  deBrujin et al., 201538 (1989)  Association of AF with incident dementia in people > 55 years. Population based prospective cohort study, Netherlands  n = 6514  AF: 12-lead ECG, Cognition: 3MSE, GMSS, CAMDEX-R  Incident AF was associated with risk of dementia in participants <67 years: HR 1.81 (95% CI 1.11- 2.94) adjusted for age, sex, diabetes mellitus, smoking, total cholesterol and HDL, lipid-lowering medication, BP, BP lowering medication, educational level, ever use of oral anticoagulation, CAD, HF, ApoE4.  age 68.3 ± 8.5 (no AF) & 75.7 ± 8.1 (AF), male 41.6% (no AF) & 49.4% (AF), follow-up 20 years  MMSE, Modified Mini-Mental State Examination; DSST, Digit Symbol Substitution Test; GMSS, Geriatric Mental State Schedule; CAMDEX-R, Cambridge Examination for Mental Disorders of the Elderly; NINDS-ADRDA, National Institute of Neurological Disorders and Alzheimer’s Disease and Related Disorders; NINDS-AIREN, Association Internationale pour la Recherche et l'Enseignement en Neurosciences; HTN, hypertension; BMI, Body Mass Index; CAD, coronary artery disease; ACE, angiotensin-converting enzyme; TIA, transient ischaemic attack; HF, heart failure. A systematic review by Santangeli et al.39 comprised eight prospective studies including more than 77 000 patients of whom 11 700 (17%) had AF.33,35,36,40–44 The authors evaluated the association between AF and the incidence of dementia in patients not suffering an acute stroke and with normal cognitive function at baseline. After adjusting for confounders, an independent risk of incident dementia was demonstrated in AF patients with a HR 1.4 (95% CI 1.2–1.7). An even larger systematic review published in 2013 by Kalantarian assessed the association of AF with cognitive decline or dementia. Including prospective and non-prospective studies, mainly using MMSE and DSM-III or IV criteria, the risk for cognitive impairment was more than doubled in AF patients with a history of stroke [RR 2.70 (95% CI 1.82–4.00)]. In addition, there was a significantly increased risk for cognitive decline in patients with or without a history of stroke [RR 1.40 (95% CI 1.19–1.64)], as well as in AF patients without a history of stroke [RR 1.37 (95% CI 1.08–1.73)].45 AF-related ischaemic stroke causes cognitive decline AF is associated with a four- to five-fold risk of ischaemic stroke, and at least 15% of all strokes are related to AF.11,15 The fact that ischaemic strokes may cause cognitive decline is widely accepted and part of the etiological concept of ‘post-stroke’, and ‘vascular’ dementia.46,47 New-onset dementia was reported in up to 33% of all stroke patients within 5 years.47 In addition to manifest (or ‘overt’) ischaemic stroke, so called clinically ‘silent’ or ‘covert’ strokes contribute to cognitive decline.48,49 Silent brain infarction is common in the general population (7–28%) and can be found in 28–90% of AF patients. Moreover, AF was significantly associated with silent brain infarction in six cohort studies or case series, with odds ratios (ORs) ranging from 2.2 to 7.2.50 AF may cause cognitive dysfunction independent of ischaemic stroke Several prospective studies and two meta-analyses39,45 postulated an increased risk of dementia in AF-patients independent from AF-related (clinically overt) ischaemic stroke32–38 (see Table 2). Unfortunately, in the majority of studies investigating the association of AF and cognitive decline or dementia, no brain imaging was performed to estimate the potential impact of clinically ‘silent’ strokes.32,33,35–38 However, there is growing evidence demonstrating a potential role of cerebral hypoperfusion, chronic inflammation, as well as endothelial dysfunction in dementia,47 and similar mechanisms may be involved in AF-related cognitive decline. Another piece of evidence comes from a case control study in Germany, postulating that AF alters cognitive function independent of stroke.34 The authors assessed memory function (i.e. by using a detailed test battery for cognitive function) and measured hippocampal volumes (by MRI) in stroke-free patients with (n = 87) or without atrial fibrillation (n = 446). AF patients included in this study were relatively young (mean age 60 years). Presence of AF was independently related to poor performance in learning and memory, as well as attention and executive functions. In addition, smaller hippocampal volumes were found in AF patients. Somewhat surprisingly, the authors hypothesised that hippocampal atrophy may relate to microembolism at an early stage that might affect the entire cerebral tissue.34 However, in our opinion, this assumption can be challenged because brain MRI did not demonstrate white matter temporal hyperintensities in these patients. AF-related hypoperfusion of the brain – the ‘CATCH’ hypothesis An AF-related reduction of cardiac output (through beat-to-beat-variability and subsequent reduced left-ventricular output) may lead to chronic hypoperfusion of the brain and hypoxia, as similarly reported for heart failure (see Figure 1).27,51–54 As an example, the Framingham Offspring Study evaluated the association between heart failure-related cerebral hypoperfusion and cognitive decline in 1114 patients by using differentiated neuropsychological testing and brain MRI. Comparing left ventricular ejection fraction (LVEF) quintiles, the lowest LVEF was associated with poorer cognitive performance.53 In addition, even subclinical diastolic dysfunction has been linked to dementia.54 A transcranial Doppler study including 187 heart failure patients (minimum NYHA II) associated cognitive performance with cerebral blood flow velocity. The study demonstrates significantly lower cerebral blood flow velocity in heart failure patients with AF, compared to heart failure patients without AF, associated with worse performance in some cognitive domains.55 Figure 1 View largeDownload slide Candidate pathophysiologic mechanisms of atrial fibrillation-related cognitive decline and dementia. Figure 1 View largeDownload slide Candidate pathophysiologic mechanisms of atrial fibrillation-related cognitive decline and dementia. Based on an animal model of cerebral hypoperfusion demonstrating that hypoperfusion leads to chronic suboptimal delivery of nutrients and reduced clearance of amyloid-beta and other toxins, de la Torre formulated the CATCH hypothesis (ie., critically attained threshold of cerebral hypoperfusion).56,57 However, in our view this hypothesis cannot explain the majority of dementias because cerebral autoregulation is expected to maintain cerebral blood flow during a wide blood pressure range and evidence is lacking that cerebral autoregulation is dysfunctional in the majority of AF-patients.58 Even in patients with disturbed cerebral autoregulation, a critical dysregulation of blood pressure would be needed to have an impact on brain perfusion. That is not the case in the majority of AF patients, since AF may reduce (preserved) cardiac ejection fraction by only about one fifth.59 Nevertheless, AF is an independent risk factor for (chronic) heart failure, and about 30% of all AF patients suffer from (chronic) heart failure with reduced ejection fraction.60 AF-related systemic inflammation Two comprehensive overviews of available case-control studies and prospective cohort studies summarise potential mechanisms linking initiation and perpetuation of AF to systemic inflammation, mediated by CRP, interleukin (IL) IL-2, IL-6, and IL-8, tumor necrosis factor-alpha (TNF-α) or monocyte-chemoattractant protein-161,62 amongst others. Furthermore, there is growing evidence that AF itself induces the release of CRP and inflammatory cytokines, in turn leading to platelet activation. As shown in case-series including AF patients undergoing left atrial catheter ablation,63,64 highly-sensitive-CRP (hs-CRP) levels and IL-6 levels were reduced after restoration of sinus rhythm. In addition, AF also induces endothelial dysfunction and is associated with increased coagulation activity, as indicated by higher levels of D-dimer, fibrinogen, prothrombin fragment 1 and 2, platelet factor-4, thromboglobulin, and von Willebrand factor.61,65,66 AF-induced chronic inflammation may cause cognitive decline via malfunctioning of cerebrovascular regulation, which has been linked to Alzheimer’s and vascular dementia.67,68 In a cohort study of 370 patients with persistent or permanent non-valvular AF, TNF-α baseline blood-levels were a significant predictor of ischaemic stroke during a follow-up of 3 years.69 Animal research on the sphingosine-1-phosphate (S1P) signaling pathway has recently shed more light on the potential relationship of inflammation and dementia: S1P signaling has emerged as an important pathway with vasoconstrictive effects on cerebral arteries. Factors modulating the sphingosine kinase 1 (Sphk 1) activity—the core element of this pathway—alter myogenic response in smooth muscle cells and in turn might contribute to critical hypoperfusion of the brain.70,71 TNF-α is a well-described activator of Sphk1, which phosphorylates sphingosine to sphingosine-1-phosphate (SP1) and has become a hallmark of cerebrovascular72 and cardiovascular73 disease. The pro-constrictive effects of S1P are mediated via the S1P2 receptor, which activates RhoA/Rho-kinase and ultimately inhibits myosin light chain phosphatase, which leads to a higher sensitivity to intracellular calcium. In an animal model, the application of TNF-α antagonist etanercept induced a reversion of TNF-α/sphingosine-1-phospahte mediated cerebral vasoconstriction.71,74 While this finding may point to potential novel treatment targets, these data are still lacking confirmation from large prospective studies in humans. Does treatment of AF or stroke prevention in AF patients prevent cognitive decline? Anticoagulation Effective oral anticoagulation reduces the burden of AF-related embolic strokes in patients with additional stroke risk factors and is strongly recommended by current guidelines.11 Therefore, it is plausible to assume that effective anticoagulation of AF-patients should also lead to preserved cognitive function. In support of this notion, it was demonstrated that a low time in the therapeutic range in warfarin treated AF patients significantly increased the risk of incident dementia.75 Furthermore, the comparison of warfarin treated AF patients and warfarin treated non-AF patients showed that AF patients had a higher risk for dementia than warfarin treated patients for other reasons,76 further underlining the impact of AF on cognition independent from stroke (for more details see Table 3,75–82). Nevertheless, until now there is no convincing prospective evidence that effective oral anticoagulation may prevent dementia in AF patients82 and large studies with longer follow up are needed to clarify the impact of anticoagulation on cognition, as described below. Table 3 Impact of oral anticoagulation75,76,79–82 as well as rate- or rhythm control77,78 on cognitive function in AF patients Author (Enrollment)  Cohort and study design  Cohort characteristics  Definition of dementia  Main findings  Chung et al. 200575 (1995–1999)  Cognition in rate vs. rhythm control in AF patients enrolled in AFFIRM.United States/Canada.  n = 245,  MMSE  No significant difference of MMSE in AF patients randomized to rhythm or rate control in the adjusted analysis (but no risk ratios provided in the publication).  age 69.7 ± 9, male 61%, follow-up 5 years  Bunch et al., 201176 (1994)  Impact of catheter ablation for AF on long-term risk of dementia. Cohort study based on a database, United States.  n = 37 908  ICD-9  Ablated patients had a significantly lower risk of dementia compared to AF patients without ablation: HR 2.81 (95% CI not provided; p < 0.001) adjusted for age, sex, diabetes, HTN, hyperlipidemia, CHF, renal failure, TIA history, CVA, MI.  age 66.0 ± 13.3 years, male 60.8%, Caucasian 89%, follow up 3 years  Jacobs et al., 201477 (1994)  Incidence of dementia in warfarin-treated AF patients with low vs. high time in the therapeutic range. Retrospective population-based study, United States  n = 2605  ICD-9  Low time in the therapeutic range increases the risk of incident dementia HR 5.34 (CI 95% 2–12) adjusted for age, sex, HTN, hyperlipidemia, diabetes mellitus, smoking, CHF, CAD, coronary bypass, myocardial infarction, renal failure.  age 73.7 ± 10.8 years, male 54%, follow-up 4 years  Mavaddat et al., 201478 (2001–2004)  Cognitive function in the Birmingham Atrial Fibrillation Treatment of the Aged Study. Prospective randomized open – label trial, United Kingdom  n = 973  MMSE  Not significantly improved cognition in warfarin-treated AF patients at the end of follow- up. Adjusted analysis for baseline short orientation-memory concentration test, age, sex, and previous stroke or TIA.  age 81.5 ± 4.3 years, male 55%, follow-up 33 months  Jacobs et al., 201679 (2010–2014)  Incidence of dementia in NOAC vs. warfarin users because of AF, thrombosis or valvular heart disease. Retrospective population-based study, United States  n = 5254  ICD-9, ICD-10  NOAC patients had a lower risk of dementia/stroke/TIA compared with warfarin-treated patients: HR 0.49 (95% CI 0.35–0.69) adjusted for age, sex, HTN, hyperlipidemia, diabetes mellitus, CHF, CAD, coronary bypass, stroke/TIA.  age 72.4 ± 10.9 years, male 59%, follow-up warfarin 309 days, NOACs 185 days  Bo et al., 201680 (2010–2013)  Effects of anticoagulation on AF patients aged ≥65 years, discharged from geriatric ward. Retrospective cohort study, Italy  n = 980  SPMSQ  Anticoagulation was associated with reduced mortality and better cognitive status: OR 2.29 (95% CI 1.47–3.57) adjusted for age, sex, congestive heart failure; HTN; aged≥75 years, diabetes, stroke, systemic embolism, vascular disease, abnormal renal/liver function, bleeding history, labile INR, drugs/alcohol.  age 83.4 ± 6.7 years, male 40%, follow-up 571 days  Bunch et al., 201681 (1994)  Prevalence of dementia in warfarin treated AF-patients and warfarin treated non-AF patients. Retrospective cohort study, United States  n = 10 537  ICD-9 + ICD-10  Warfarin treated AF patients with had a higher risk for dementia than warfarin treated non-AF patients HR = 2.42 (95% CI 1.85–3.18) adjusted analysis for age, sex, HTN, hyperlipidemia, diabetes, smoking, CHF, stroke, TIA, CAD, renal failure, prior CABG, PCI, bleed, malignancy, fall, and sleep apnea.  age 69.3 ± 10.9 years, male 52%, follow-up 2021 days  Moffitt et al., 201682 (studies from 1998–2015)  Meta-analysis of randomized controlled trials regarding cognition or dementia in patients with AF or atrial flutter.  n = 15876  MMSE  Potential benefit of anticoagulation in comparison to controls with antiplatelet therapy in patients with AF (or atrial flutter) over time, but no definitive evidence of cognitive benefit from anticoagulation treatment.  age/men n.a., follow-up 5.9 years  Author (Enrollment)  Cohort and study design  Cohort characteristics  Definition of dementia  Main findings  Chung et al. 200575 (1995–1999)  Cognition in rate vs. rhythm control in AF patients enrolled in AFFIRM.United States/Canada.  n = 245,  MMSE  No significant difference of MMSE in AF patients randomized to rhythm or rate control in the adjusted analysis (but no risk ratios provided in the publication).  age 69.7 ± 9, male 61%, follow-up 5 years  Bunch et al., 201176 (1994)  Impact of catheter ablation for AF on long-term risk of dementia. Cohort study based on a database, United States.  n = 37 908  ICD-9  Ablated patients had a significantly lower risk of dementia compared to AF patients without ablation: HR 2.81 (95% CI not provided; p < 0.001) adjusted for age, sex, diabetes, HTN, hyperlipidemia, CHF, renal failure, TIA history, CVA, MI.  age 66.0 ± 13.3 years, male 60.8%, Caucasian 89%, follow up 3 years  Jacobs et al., 201477 (1994)  Incidence of dementia in warfarin-treated AF patients with low vs. high time in the therapeutic range. Retrospective population-based study, United States  n = 2605  ICD-9  Low time in the therapeutic range increases the risk of incident dementia HR 5.34 (CI 95% 2–12) adjusted for age, sex, HTN, hyperlipidemia, diabetes mellitus, smoking, CHF, CAD, coronary bypass, myocardial infarction, renal failure.  age 73.7 ± 10.8 years, male 54%, follow-up 4 years  Mavaddat et al., 201478 (2001–2004)  Cognitive function in the Birmingham Atrial Fibrillation Treatment of the Aged Study. Prospective randomized open – label trial, United Kingdom  n = 973  MMSE  Not significantly improved cognition in warfarin-treated AF patients at the end of follow- up. Adjusted analysis for baseline short orientation-memory concentration test, age, sex, and previous stroke or TIA.  age 81.5 ± 4.3 years, male 55%, follow-up 33 months  Jacobs et al., 201679 (2010–2014)  Incidence of dementia in NOAC vs. warfarin users because of AF, thrombosis or valvular heart disease. Retrospective population-based study, United States  n = 5254  ICD-9, ICD-10  NOAC patients had a lower risk of dementia/stroke/TIA compared with warfarin-treated patients: HR 0.49 (95% CI 0.35–0.69) adjusted for age, sex, HTN, hyperlipidemia, diabetes mellitus, CHF, CAD, coronary bypass, stroke/TIA.  age 72.4 ± 10.9 years, male 59%, follow-up warfarin 309 days, NOACs 185 days  Bo et al., 201680 (2010–2013)  Effects of anticoagulation on AF patients aged ≥65 years, discharged from geriatric ward. Retrospective cohort study, Italy  n = 980  SPMSQ  Anticoagulation was associated with reduced mortality and better cognitive status: OR 2.29 (95% CI 1.47–3.57) adjusted for age, sex, congestive heart failure; HTN; aged≥75 years, diabetes, stroke, systemic embolism, vascular disease, abnormal renal/liver function, bleeding history, labile INR, drugs/alcohol.  age 83.4 ± 6.7 years, male 40%, follow-up 571 days  Bunch et al., 201681 (1994)  Prevalence of dementia in warfarin treated AF-patients and warfarin treated non-AF patients. Retrospective cohort study, United States  n = 10 537  ICD-9 + ICD-10  Warfarin treated AF patients with had a higher risk for dementia than warfarin treated non-AF patients HR = 2.42 (95% CI 1.85–3.18) adjusted analysis for age, sex, HTN, hyperlipidemia, diabetes, smoking, CHF, stroke, TIA, CAD, renal failure, prior CABG, PCI, bleed, malignancy, fall, and sleep apnea.  age 69.3 ± 10.9 years, male 52%, follow-up 2021 days  Moffitt et al., 201682 (studies from 1998–2015)  Meta-analysis of randomized controlled trials regarding cognition or dementia in patients with AF or atrial flutter.  n = 15876  MMSE  Potential benefit of anticoagulation in comparison to controls with antiplatelet therapy in patients with AF (or atrial flutter) over time, but no definitive evidence of cognitive benefit from anticoagulation treatment.  age/men n.a., follow-up 5.9 years  ICD, International Classification of Disease; MMSE, Mini Mental state Examination; CABG, coronary artery bypass graft surgery; PCI, percutaneous coronary intervention; HTN, hypertension; CHF, chronic heart failure; TIA, transient ischaemic attack; CAD, coronary artery disease; CVA, cerebrovascular accidents; MI, myocardial infarction; INR, international normalized ratio. Rhythm control therapy The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was the so far largest randomized trial comparing rate vs. rhythm control strategy. While the primary endpoint of AFFIRM was negative, a substudy including 245 AF patients did not show any difference regarding MMSE scores during a mean follow-up of 3.5 years.77 Best available evidence regarding left atrial catheter ablation is derived from the prospective Intermountain Atrial Fibrillation study,78 a case–control study based on a large healthcare database. Having included 16 848 patients with no history of AF, 4212 patients with symptomatic AF undergoing left atrial catheter ablation, and 16 848 non-ablated AF patients, this epidemiologic study is able to report associations but cannot establish causality. Over a period of 3 years, new onset AD was reported in 0.2% of AF patients who underwent left atrial catheter ablation compared to 0.9% of the non-ablated AF patients and 0.5% of the non-AF patients (p < 0.001). Other forms of incident dementia occurred in 0.4% of the AF ablation patients compared to 1.9% of the non-ablated AF patients and 0.7% of the non-AF patients (p < 0.001). Dementia was diagnosed by neurologists according to ICD-9. Unfortunately, anticoagulation rates and individualized medical therapy were not reported. At present, a large randomized trial is ongoing, investigating the potential benefit of early rhythm control in AF patients. The Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST) enrolled and randomized 2745 AF patients to rhythm control therapy based on antiarrhythmic drugs and catheter ablation or usual care following the 2010 European Society of Cardiology (ESC) guidelines. Cognitive function after 24 months of follow up is a secondary endpoint of EAST83 (Table 4) which will probably be reported in early 2019. Table 4 Ongoing AF studies focusing on cognition Study (Clintrials.gov)  Study design  Endpoint regarding cognition  EAST  Prospective, randomized, open, blinded outcome assessment trial. n = 2810  Secondary endpoint: MoCA 24 months after randomization.  NCT01288352  Early, comprehensive, rhythm control therapy in prevention of adverse cardiovascular outcomes in patients with AF compared to usual care.  BRAIN-AF  Prospective, randomized, double blind, efficacy study. n = 6396  Secondary endpoint: 3MS, MMSE and MoCA at any of the follow-up visits.  NCT02387229  Acetylsalicylic acid compared to rivaroxaban 15mg per day with regard to stroke prevention plus cognitive decline in non-valvular AF patients.  GIRAF  Prospective, randomized, open, blinded outcome assessment, efficacy study. n = 200  Primary outcome: cognitive impairment (MoCA + NINDS-CSN-Vascular Cognitive Impairment Harmonization) after 1 year and at the end of follow-up.  NCT01994265  Trial for the prevention of cognitive impairment in atrial fibrillation patients treated with dabigatran (150mg bid) or warfarin (targeting INR 2–3) for 2 years.  DIAL-F  Prospective case- control study. n = 888  Primary outcome: improvement or no-improvement in MoCA at baseline and at the 2-year follow-up.  NCT01816308  Incidence of cognitive impairments between AF patients undergoing either catheter ablation or remaining on anti-arrhythmic drugs at a 2-year follow-up.  SWISS-AF  Prospective observational, multicenter cohort study. n = 2600  Yearly clinical examination of neurocognitive function, MRI at baseline and 2 years follow-up.  NCT02105844  To increase knowledge on structural brain damage, the incidence and underlying mechanisms of cognitive decline in patients with atrial fibrillation.  Study (Clintrials.gov)  Study design  Endpoint regarding cognition  EAST  Prospective, randomized, open, blinded outcome assessment trial. n = 2810  Secondary endpoint: MoCA 24 months after randomization.  NCT01288352  Early, comprehensive, rhythm control therapy in prevention of adverse cardiovascular outcomes in patients with AF compared to usual care.  BRAIN-AF  Prospective, randomized, double blind, efficacy study. n = 6396  Secondary endpoint: 3MS, MMSE and MoCA at any of the follow-up visits.  NCT02387229  Acetylsalicylic acid compared to rivaroxaban 15mg per day with regard to stroke prevention plus cognitive decline in non-valvular AF patients.  GIRAF  Prospective, randomized, open, blinded outcome assessment, efficacy study. n = 200  Primary outcome: cognitive impairment (MoCA + NINDS-CSN-Vascular Cognitive Impairment Harmonization) after 1 year and at the end of follow-up.  NCT01994265  Trial for the prevention of cognitive impairment in atrial fibrillation patients treated with dabigatran (150mg bid) or warfarin (targeting INR 2–3) for 2 years.  DIAL-F  Prospective case- control study. n = 888  Primary outcome: improvement or no-improvement in MoCA at baseline and at the 2-year follow-up.  NCT01816308  Incidence of cognitive impairments between AF patients undergoing either catheter ablation or remaining on anti-arrhythmic drugs at a 2-year follow-up.  SWISS-AF  Prospective observational, multicenter cohort study. n = 2600  Yearly clinical examination of neurocognitive function, MRI at baseline and 2 years follow-up.  NCT02105844  To increase knowledge on structural brain damage, the incidence and underlying mechanisms of cognitive decline in patients with atrial fibrillation.  EAST, Early Treatment of Atrial Fibrillation for Stroke Prevention Trial; BRAIN-AF, Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation; GIRAF, Cognitive Impairment Related to Atrial Fibrillation Prevention Trial; DIAL-F, Cognitive Impairment in Atrial Fibrillation; SWISS-AF, Swiss Atrial Fibrillation Cohort Study; MoCA, Montreal Cognitive Assessment; 3MS, modified Mini-Mental-State; MMSE, Mini-Mental-State-Examination; NINDS-CSN, National Institute of Neurological Disorders and Stroke-Canadian Stroke Network. Anti-inflammatory drugs Since inflammatory pathways have been implicated as mechanisms leading to cognitive decline in AF patients, it is tempting to speculate whether anti-inflammatory drugs or statins may preserve cognitive function in these patients. However, it should be noted that until now no specific studies have been performed in AF patients to test this hypothesis. Therefore, we have to infer from studies in patients with high vascular risk. Statins have anti-inflammatory properties.84,85 In a substudy of the Cholesterol and Recurrent Events trial (CARE) randomizing 4150 patients 1:1 to placebo or 40 mg pravastatin per day, a significant increase in CRP levels in the placebo group was detected after a follow-up of 5 years.86 A retrospective National Health Insurance Research Database analysis, including more than 51 000 Taiwanese AF patients and 200 000 controls without dementia, recently demonstrated an association of statin treatment with a reduced risk for non-vascular dementia [HR 0.83 (95% CI 0.80–0.86)] during a follow-up of 10 years.87 This protective effect of statins was obviously not AF-specific, because pooled analyses from eight non-randomized studies88–96 including more than 23 400 non-AF statin-treated patients reported a HR of 0.71 (95% CI 0.61–0.82) for dementia during a follow-up of 3 to 24 years.97 In contrast, however, an ‘antidementive’ effect of statins was not observed in the HPS and the PROSPER trial, evaluating non-AF patients aged 70 years or older randomized to either 40 mg of simvastatin (HPS) or 40 mg pravastatin (PROSPER) per day or placebo during a follow up of 5 years.98 Another potential treatment target might be TNF-α mediated neurotoxicity. Perispinal application of etanercept in more than 600 stroke-patients resulted in a significant improvement of cognition and psychological/behavioral function according to a retrospective chart-analysis.99 However, the study has several methodological weaknesses, and the results have to be confirmed in a controlled setting. Large ongoing AF trials focusing on cognition The advent of non-vitamin K dependent oral anticoagulants (NOACs) and their increasing use in clinical practice will probably help to shed more light on the impact of oral anticoagulation on cognitive function in AF patients. While comparing rivaroxaban to acetylsalicylic acid in AF patients with low risk of stroke, the prospective, randomized, double-blind Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF) study has a secondary endpoint on cognition. Moreover, the primary endpoint of the Cognitive Impairment Related to Atrial Fibrillation Prevention (GIRAF) study comparing dabigatran to warfarin is cognitive function over a period of 2 years. Besides the aforementioned EAST study,83 the primary endpoint of the case-control study Cognitive Impairment in Atrial Fibrillation (DIAL-F)—comparing catheter ablation to anti-arrhythmic drug treatment—is focusing on rhythm control and cognitive decline. Moreover, the large observational SWISS-AF study includes neuropsychological testing in AF patients undergoing repeated brain imaging (Table 4). Implications for the future Long-term longitudinal studies are needed to unequivocally address the impact of AF on cognition (as opposed to other concomitant co-morbidities and risk factors). In more detail, humoral or blood-flow dependent mechanisms by which AF may contribute to cognitive decline should be deciphered. In addition, large AF treatment trials should focus on cognition and dementia as an independent endpoint. Future trials should further clarify whether serial assessment of cardiac function and cardiac rhythm may be beneficial in subjects presenting with cognitive impairment. Whether isolated atrial amyloidosis not only increases the risk of AF100 but is also linked to the amyloid deposits observed in Alzheimeŕs dementia needs further investigation. Conclusions AF and dementia are both frequent diseases with substantial socioeconomic impact on the ageing society. Despite of overlapping cardiovascular risk factors, growing evidence from prospective studies supports the hypothesis that AF is an independent risk factor for cognitive decline and dementia, also including AD. Potential pathomechanisms of AF-related dementia are obviously AF-related (clinically overt or silent) strokes and systemic inflammation. Whether chronic hypoperfusion of the brain is relevant for the development of Alzheimer’s remains unclear, in particular when considering the preventive effect of antihypertensive drugs. Well-designed randomized trials, accompanied by a standardised cognitive assessment, are urgently needed to identify (novel) treatment options to prevent cognitive decline in AF patients. Acknowledgements We thank Julia Herde for reviewing the manuscript and Bob Siegerink for supporting the chapter on epidemiology (Center for Stroke Research Berlin, Germany). Conflict of interest: Joanna Dietzel reports no conflict of interests. Karl Georg Haeusler reports speaker's honoraria, consulting fees, lecture honoraria, and study grants from Bayer Healthcare, Boehringer Ingelheim, Sanofi, Medtronic, Pfizer, and Bristol-Myers Squibb. Matthias Endres reports lecture fees and study grants by Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Ever, Glaxo Smith Kline, MSD, Novartis, and Pfizer. Funding K.G.H. received funding from the BMBF (Center for Stroke Research Berlin) and DZHK. M.E. has received funding from the DFG (NeuroCure, SFB TR 43, KFO 247), BMBF (Center for Stroke Research Berlin), DZHK, EU (European Stroke Network, WakeUp, Counterstroke), Corona Foundation (Vascular Senescence); Fondation Leducq. References 1 Cohen MB, Mather PJ. A review of the association between congestive heart failure and cognitive impairment. Am J Geriatr Cardiol  2007; 16: 171– 4. Google Scholar CrossRef Search ADS PubMed  2 Thacker EL, Gillett SR, Wadley VG, Unverzagt FW, Judd SE, McClure LA et al.   The American Heart Association Life's Simple 7 and incident cognitive impairment: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study. J Am Heart Assoc  2014;11; 3: e000635. Google Scholar CrossRef Search ADS PubMed  3 Wu YT, Fratiglioni L, Matthews FE, Lobo A, Breteler MM, Skoog I et al.   Dementia in western Europe: epidemiological evidence and implications for policy making. Lancet Neurol  2016; 15: 116– 24. Google Scholar CrossRef Search ADS PubMed  4 Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement  2013; 9: 63– 75.e2. Google Scholar CrossRef Search ADS PubMed  5 Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol  2014; 16: 213– 20. Google Scholar CrossRef Search ADS   6 Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH et al.   Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J  2006; 27: 949– 53. Google Scholar CrossRef Search ADS PubMed  7 Connolly A, Gaehl E, Martin H, Morris J, Purandare N. Underdiagnosis of dementia in primary care: variations in the observed prevalence and comparisons to the expected prevalence. Aging Ment Health  2011; 15: 978– 84. Google Scholar CrossRef Search ADS PubMed  8 Erkinjuntti T, Ostbye T, Steenhuis R, Hachinski V. The effect of different diagnostic criteria on the prevalence of dementia. N Engl J Med  1997; 337: 1667– 74. Google Scholar CrossRef Search ADS PubMed  9 Wancata J, Börjesson-Hanson A, Ostling S, Sjögren K, Skoog I. Diagnostic criteria influence dementia prevalence. Am J Geriatr Psychiatry  2007; 15: 1034– 45. Google Scholar CrossRef Search ADS PubMed  10 Chen Y, Szoeke C, Woodward M. Performance of the different proposed criteria for the diagnosis of mild cognitive impairment and Alzheimer's disease: data from the Australian imaging, biomarkers and lifestyle study of aging. Alzheimers Dement  2013; 9: P755– 6. Google Scholar CrossRef Search ADS   11 Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B et al.   2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace  2016; 8: 1609– 78. Google Scholar CrossRef Search ADS   12 Svennberg E, Engdahl J, Al-Khalili F, Friberg L, Frykman V, Rosenqvist M. Mass screening for untreated atrial fibrillation: the STROKESTOP study. Circulation  2015; 131: 2176– 84. Google Scholar CrossRef Search ADS PubMed  13 Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S et al.   Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). European Heart Rhythm Association1; European Association for Cardio-Thoracic Surgery; ESC Committee for Practice Guidelines. Europace  2010; 12: 1360– 420. Google Scholar CrossRef Search ADS PubMed  14 Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA et al.   ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace  2006; 8: 651– 745. Google Scholar CrossRef Search ADS PubMed  15 Glotzer TV, Ziegler PD. Cryptogenic stroke: is silent atrial fibrillation the culprit? Heart Rhythm  2015; 12: 234– 41. Google Scholar CrossRef Search ADS PubMed  16 Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA et al.   CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med  2014; 370: 2478– 86. Google Scholar CrossRef Search ADS PubMed  17 Lowres N, Neubeck L, Redfern J, Freedman SB. Screening to identify unknown atrial fibrillation. A systematic review. Thromb Haemost  2013; 110: 213– 22. Google Scholar CrossRef Search ADS PubMed  18 Dussault C, Toeg H, Nathan M, Wang ZJ, Roux JF, Secemsky E. Electrocardiographic monitoring for detecting atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol  2015; 8: 263– 9. Google Scholar CrossRef Search ADS PubMed  19 Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol  2004; 61: 661– 6. Google Scholar CrossRef Search ADS PubMed  20 Iguchi Y, Kimura K, Aoki J, Kobayashi K, Terasawa Y, Sakai K et al.   Prevalence of atrial fibrillation in community-dwelling Japanese aged 40 years or older in Japan: analysis of 41,436 non-employee residents in Kurashiki-city. Circ J  2008; 72: 909– 13. Google Scholar CrossRef Search ADS PubMed  21 Hailpern SM, Melamed ML, Cohen HW, Hostetter TH. Moderate chronic kidney disease and cognitive function in adults 20 to 59 years of age: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol  2007; 18: 2205– 13. Google Scholar CrossRef Search ADS PubMed  22 Liao JN, Chao TF, Liu CJ, Wang KL, Chen SJ, Lin YJ et al.   Incidence and risk factors for new-onset atrial fibrillation among patients with end-stage renal disease undergoing renal replacement therapy. Kidney Int  2015; 87: 1209– 15. Google Scholar CrossRef Search ADS PubMed  23 Spira AP, Blackwell T, Stone KL, Redline S, Cauley JA, Ancoli-Israel S et al.   Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc  2008; 56: 45– 50. Google Scholar CrossRef Search ADS PubMed  24 Gami AS, Hodge DO, Herges RM, Olson EJ, Nykodym J, Kara T et al.   Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol  2007; 49: 565– 71. Google Scholar CrossRef Search ADS PubMed  25 Böhm M, Schumacher H, Leong D, Mancia G, Unger T, Schmieder R et al.   Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk. Hypertension  2015; 65: 651– 61. Google Scholar CrossRef Search ADS PubMed  26 Tremblay-Gravel M, White M, Roy D, Leduc H, Wyse DG, Cadrin-Tourigny J et al.   Blood pressure and atrial fibrillation: a combined AF-CHF and AFFIRM analysis. J Cardiovasc Electrophysiol  2015; 26: 509– 14. Google Scholar CrossRef Search ADS PubMed  27 Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L. Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med  2006; 166: 1003– 8. Google Scholar CrossRef Search ADS PubMed  28 Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA  1994; 271: 840– 4. Google Scholar CrossRef Search ADS PubMed  29 Roberts RO, Knopman DS, Geda YE, Cha RH, Roger VL, Petersen RC. Coronary heart disease is associated with non-amnestic mild cognitive impairment. Neurobiol Aging  2010; 31: 1894– 902. Google Scholar CrossRef Search ADS PubMed  30 Mukamal KJ, Kuller LH, Fitzpatrick AL, Longstreth WTJr, Mittleman MA, Siscovick DS. Prospective study of alcohol consumption and risk of dementia in older adults. JAMA  2003; 289: 1405– 13. Google Scholar CrossRef Search ADS PubMed  31 Mukamal KJ, Tolstrup JS, Friberg J, Jensen G, Grønbaek M. Alcohol consumption and risk of atrial fibrillation in men and women: the Copenhagen City Heart Study. Circulation  2005; 112: 1736– 42. Google Scholar CrossRef Search ADS PubMed  32 Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study. The Rotterdam Study. Stroke  1997; 28: 316– 21. Google Scholar CrossRef Search ADS PubMed  33 Elias MF, Sullivan LM, Elias PK, Vasan RS, D'Agostino RBSr, Seshadri S et al.   Atrial fibrillation is associated with lower cognitive performance in the Framingham offspring men. J Stroke Cerebrovasc Dis  2006; 15: 214– 22. Google Scholar CrossRef Search ADS PubMed  34 Knecht S, Oelschläger C, Duning T, Lohmann H, Albers J, Stehling C et al.   Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J  2008; 29: 2125– 32. Google Scholar CrossRef Search ADS PubMed  35 Bunch TJ, Weiss JP, Crandall BG, May HT, Bair TL, Osborn JS et al.   Atrial fibrillation is independently associated with senile, vascular, and Alzheimer's dementia. Heart Rhythm  2010; 7: 433– 7. Google Scholar CrossRef Search ADS PubMed  36 Marzona I, O'Donnell M, Teo K, Gao P, Anderson C, Bosch J et al.   Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ  2012; 184: E329– 36. Google Scholar CrossRef Search ADS PubMed  37 Thacker EL, McKnight B, Psaty BM, Longstreth WTJr, Sitlani CM, Dublin S et al.   Atrial fibrillation and cognitive decline: a longitudinal cohort study. Neurology  2013; 81: 119– 25. Google Scholar CrossRef Search ADS PubMed  38 de Bruijn RF, Heeringa J, Wolters FJ, Franco OH, Stricker BH, Hofman A et al.   Association between atrial fibrillation and dementia in the general population. JAMA Neurol  2015; 72: 1288– 94. Google Scholar CrossRef Search ADS PubMed  39 Santangeli P, Di Biase L, Bai R, Mohanty S, Pump A, Cereceda Brantes M et al.   Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm  2012; 9: 1761– 8. Google Scholar CrossRef Search ADS PubMed  40 Tilvis RS, Kähönen-Väre MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE. Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci  2004; 59: 268– 74. Google Scholar CrossRef Search ADS PubMed  41 Forti P, Maioli F, Pisacane N, Rietti E, Montesi F, Ravaglia G. Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment (MCI). Arch Gerontol Geriatr  2007; 44(Suppl 1): 155– 65. Google Scholar CrossRef Search ADS PubMed  42 Marengoni A, Qiu C, Winblad B, Fratiglioni L. Atrial fibrillation, stroke and dementia in the very old: a population-based study. Neurobiol Aging  2011; 32: 1336– 7. Google Scholar CrossRef Search ADS PubMed  43 Peters R, Poulter R, Beckett N, Forette F, Fagard R, Potter J et al.   Cardiovascular and biochemical risk factors for incident dementia in the Hypertension in the Very Elderly Trial. J Hypertens  2009; 27: 2055– 62. Google Scholar CrossRef Search ADS PubMed  44 Dublin S, Anderson ML, Haneuse SJ, Heckbert SR, Crane PK, Breitner JC et al.   Atrial fibrillation and risk of dementia: a prospective cohort study. J Am Geriatr Soc  2011; 59: 1369– 75. Google Scholar CrossRef Search ADS PubMed  45 Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med  2013; 158: 338– 46. Google Scholar CrossRef Search ADS PubMed  46 Leys D, Hénon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol  2005; 4: 752– 9. Google Scholar CrossRef Search ADS PubMed  47 Poggesi A, Inzitari D, Pantoni L. Atrial fibrillation and cognition: epidemiological data and possible mechanisms. Stroke  2015; 46: 3316– 21. Google Scholar CrossRef Search ADS PubMed  48 Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ  2010;26; 341: c3666. Google Scholar CrossRef Search ADS PubMed  49 Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol  2015; 11: 157– 65. Google Scholar CrossRef Search ADS PubMed  50 Haeusler KG, Wilson D, Fiebach JB, Kirchhof P, Werring DJ. Brain MRI to personalise atrial fibrillation therapy: current evidence and perspectives. Heart  2014; 100: 1408– 13. Google Scholar CrossRef Search ADS PubMed  51 Haeusler KG, Laufs U, Endres M. Chronic heart failure and ischemic stroke. Stroke  2011; 42: 2977– 82. Google Scholar CrossRef Search ADS PubMed  52 Zuccalà G, Cattel C, Manes-Gravina E, Di Niro MG, Cocchi A, Bernabei R. Left ventricular dysfunction: a clue to cognitive impairment in older patients with heart failure. J Neurol Neurosurg Psychiatry  1997; 63: 509– 12. Google Scholar CrossRef Search ADS PubMed  53 Jefferson AL, Himali JJ, Au R, Seshadri S, Decarli C, O'Donnell CJ et al.   Relation of left ventricular ejection fraction to cognitive aging (from the Framingham Heart Study). Am J Cardiol  2011; 108: 1346– 51. Google Scholar CrossRef Search ADS PubMed  54 de Bruijn RF, Portegies ML, Leening MJ, Bos MJ, Hofman A, van der Lugt A et al.   Subclinical cardiac dysfunction increases the risk of stroke and dementia: the Rotterdam Study. Neurology  2015; 84: 833– 40. Google Scholar CrossRef Search ADS PubMed  55 Alosco ML, Spitznagel MB, Sweet LH, Josephson R, Hughes J, Gunstad J. Atrial fibrillation exacerbates cognitive dysfunction and cerebral perfusion in heart failure. Pacing Clin Electrophysiol  2015; 38: 178– 86. Google Scholar CrossRef Search ADS PubMed  56 de la Torre JC. Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesis. Neurobiol Aging  2000; 21: 331– 42. Google Scholar CrossRef Search ADS PubMed  57 de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke  2002; 33: 1152– 62. Google Scholar CrossRef Search ADS PubMed  58 Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res  1990; 66: 8– 17. Google Scholar CrossRef Search ADS PubMed  59 Stulak JM, Dearani JA, Daly RC, Zehr KJ, Sundt TMIII, Schaff HV. Left ventricular dysfunction in atrial fibrillation: restoration of sinus rhythm by the Cox-maze procedure significantly improves systolic function and functional status. Ann Thorac Surg  2006; 82: 494– 500. Google Scholar CrossRef Search ADS PubMed  60 Nabauer M, Gerth A, Limbourg T, Schneider S, Oeff M, Kirchhof P et al.   The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace  2009; 11: 423– 34. Google Scholar CrossRef Search ADS PubMed  61 Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol  2012; 60: 2263– 70. Google Scholar CrossRef Search ADS PubMed  62 Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol  2007; 50: 2021– 8. Google Scholar CrossRef Search ADS PubMed  63 Rotter M, Jaïs P, Vergnes MC, Nurden P, Takahashi Y, Sanders P et al.   Decline in C-reactive protein after successful ablation of long-lasting persistent atrial fibrillation. J Am Coll Cardiol  2006; 47: 1231– 3. Google Scholar CrossRef Search ADS PubMed  64 Marcus GM, Smith LM, Ordovas K, Scheinman MM, Kim AM, Badhwar N et al.   Intracardiac and extracardiac markers of inflammation during atrial fibrillation. Heart Rhythm  2010; 7: 149– 154. Google Scholar CrossRef Search ADS PubMed  65 Ohara K, Inoue H, Nozawa T, Hirai T, Iwasa A, Okumura K et al.   Accumulation of risk factors enhances the prothrombotic state in atrial fibrillation. Int J Cardiol  2008; 126: 316– 21. Google Scholar CrossRef Search ADS PubMed  66 Kallergis EM, Manios EG, Kanoupakis EM, Mavrakis HE, Kolyvaki SG, Lyrarakis GM et al.   The role of the post-cardioversion time course of hs-CRP levels in clarifying the relationship between inflammation and persistence of atrial fibrillation. Heart  2008; 94: 200– 4. Google Scholar CrossRef Search ADS PubMed  67 Bou Khalil R, Khoury E, Koussa S. Linking multiple pathogenic pathways in Alzheimer's disease. World J Psychiatry  2016;22; 6: 208– 14. Google Scholar CrossRef Search ADS PubMed  68 Wersching H, Duning T, Lohmann H, Mohammadi S, Stehling C, Fobker M et al.   Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology  2010; 74: 1022– 9. Google Scholar CrossRef Search ADS PubMed  69 Pinto A, Tuttolomondo A, Casuccio A, Di Raimondo D, Di Sciacca R, Arnao V et al.   Immuno-inflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF). Clin Sci (Lond)  2009; 116: 781– 9. Google Scholar CrossRef Search ADS PubMed  70 Bolz SS, Vogel L, Sollinger D, Derwand R, Boer C, Pitson SM et al.   Sphingosine kinase modulates microvascular tone and myogenic responses through activation of RhoA/Rho kinase. Circulation  2003; 108: 342– 7. Google Scholar CrossRef Search ADS PubMed  71 Yang J, Noyan-Ashraf MH, Meissner A, Voigtlaender-Bolz J, Kroetsch JT, Foltz W et al.   Proximal cerebral arteries develop myogenic responsiveness in heart failure via tumor necrosis factor-α-dependent activation of sphingosine-1-phosphate signaling. Circulation  2012; 126: 196– 206. Google Scholar CrossRef Search ADS PubMed  72 Sairanen T, Carpén O, Karjalainen-Lindsberg ML, Paetau A, Turpeinen U, Kaste M et al.   Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke  2001; 32: 1750– 8. Google Scholar CrossRef Search ADS PubMed  73 Pan JP, Liu TY, Chiang SC, Lin YK, Chou CY, Chan WL et al.   The value of plasma levels of tumor necrosis factor-alpha and interleukin-6 in predicting the severity and prognosis in patients with congestive heart failure. J Chin Med Assoc  2004; 67: 222– 8. Google Scholar PubMed  74 Yagi K, Lidington D, Wan H, Fares JC, Meissner A, Sumiyoshi M et al.   Therapeutically targeting tumor necrosis factor-α/sphingosine-1-phosphate signaling corrects myogenic reactivity in subarachnoid hemorrhage. Stroke  2015; 46: 2260– 70. Google Scholar CrossRef Search ADS PubMed  75 Jacobs V, Woller SC, Stevens S, May HT, Bair TL, Anderson JL et al.   Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm  2014; 11: 2206– 13. Google Scholar CrossRef Search ADS PubMed  76 Bunch TJ, May HT, Bair TL, Crandall BG, Cutler MJ, Day JD et al.   Atrial fibrillation patients treated with long-term warfarin anticoagulation have higher rates of all dementia types compared with patients receiving long-term warfarin for other indications. J Am Heart Assoc  2016; 5. e003932. Google Scholar CrossRef Search ADS PubMed  77 Chung MK, Shemanski L, Sherman DG, Greene HL, Hogan DB, Kellen JC et al.   AFFIRM Investigators. Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy. J Am Coll Cardiol  2005; 46: 1891– 9. Google Scholar CrossRef Search ADS PubMed  78 Bunch TJ, Crandall BG, Weiss JP, May HT, Bair TL, Osborn JS et al.   Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. Cardiovasc Electrophysiol  2011; 22: 839– 45. Google Scholar CrossRef Search ADS   79 Mavaddat N, Roalfe A, Fletcher K, Lip GY, Hobbs FD, Fitzmaurice D et al.   Warfarin versus aspirin for prevention of cognitive decline in atrial fibrillation: randomized controlled trial (Birmingham Atrial Fibrillation Treatment of the Aged Study). Stroke  2014; 45: 1381– 6. Google Scholar CrossRef Search ADS PubMed  80 Jacobs V, May HT, Bair TL, Crandall BG, Cutler MJ, Day JD et al.   Long-term population-based cerebral ischemic event and cognitive outcomes of direct oral anticoagulants compared with warfarin among long-term anticoagulated patients for atrial fibrillation. Am J Cardiol  2016; 118: 210– 4. Google Scholar CrossRef Search ADS PubMed  81 Bo M, Sciarrillo I, Li Puma F, Badinella Martini M, Falcone Y, Iacovino M et al.   Effects of oral anticoagulant therapy in medical inpatients ≥65 years with atrial fibrillation. Am J Cardiol  2016; 117: 590– 5. Google Scholar CrossRef Search ADS PubMed  82 Moffitt P, Lane DA, Park H, O'Connell J, Quinn TJ. Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review. Age Ageing  2016; 45: 767– 75. Google Scholar CrossRef Search ADS PubMed  83 Kirchhof P, Breithardt G, Camm AJ, Crijns HJ, Kuck KH, Vardas P et al.   Improving outcomes in patients with atrial fibrillation: rationale and design of the Early treatment of Atrial fibrillation for Stroke prevention Trial. Am Heart J  2013; 166: 442– 8. Google Scholar CrossRef Search ADS PubMed  84 Keidar S, Aviram M, Maor I, Oiknine J, Brook JG. Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein receptor activity in macrophages: in vitro and in vivo studies. Br J Clin Pharmacol  1994; 38: 513– 9. Google Scholar CrossRef Search ADS PubMed  85 Aikawa M, Rabkin E, Okada Y, Voglic SJ, Clinton SK, Brinckerhoff CE et al.   Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation  1998; 97: 2433– 44. Google Scholar CrossRef Search ADS PubMed  86 Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation  1999; 100: 230– 5. Google Scholar CrossRef Search ADS PubMed  87 Chao TF, Liu CJ, Chen SJ, Wang KL, Lin YJ, Chang SL et al.   Statins and the risk of dementia in patients with atrial fibrillation: a nationwide population-based cohort study. Int J Cardiol  2015; 196: 91– 7. Google Scholar CrossRef Search ADS PubMed  88 Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M et al.   Cache County Study investigators. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry  2005; 62: 217– 24. Google Scholar CrossRef Search ADS PubMed  89 Bettermann K, Arnold AM, Williamson J, Rapp S, Sink K, Toole JF et al.   Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study. J Stroke Cerebrovasc Dis  2012; 21: 436– 44. Google Scholar CrossRef Search ADS PubMed  90 Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry  2009; 80: 13– 7. Google Scholar CrossRef Search ADS PubMed  91 Rea TD, Breitner JC, Psaty BM, Fitzpatrick AL, Lopez OL, Newman AB et al.   Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol  2005; 62: 1047– 51. Google Scholar CrossRef Search ADS PubMed  92 Beydoun MA, Beason-Held LL, Kitner-Triolo MH, Beydoun HA, Ferrucci L, Resnick SM et al.   Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment. J Epidemiol Community Health  2011; 65: 949– 57. Google Scholar CrossRef Search ADS PubMed  93 Li G, Shofer JB, Rhew IC, Kukull WA, Peskind ER, McCormick W et al.   Age-varying association between statin use and incident Alzheimer's disease. J Am Geriatr Soc  2010; 58: 1311– 7. Google Scholar CrossRef Search ADS PubMed  94 Arvanitakis Z, Schneider JA, Wilson RS, Bienias JL, Kelly JF, Evans DA et al.   Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology  2008; 70: 1795– 802. Google Scholar CrossRef Search ADS PubMed  95 Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology  2008; 71: 344– 50. Google Scholar CrossRef Search ADS PubMed  96 Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med  2007;19; 5: 20. Google Scholar CrossRef Search ADS PubMed  97 Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc  2013; 88: 1213– 21. Google Scholar CrossRef Search ADS PubMed  98 McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev  2009; CD003160. 99 Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, DePuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs  2012; 26: 1051– 70. Google Scholar CrossRef Search ADS PubMed  100 Röcken C, Peters B, Juenemann G, Saeger W, Klein HU, Huth C et al.   Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation  2002; 106: 2091– 7. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Europace Oxford University Press

Does atrial fibrillation cause cognitive decline and dementia?

Loading next page...
 
/lp/ou_press/does-atrial-fibrillation-cause-cognitive-decline-and-dementia-h5WBC665Fr
Publisher
Oxford University Press
Copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
ISSN
1099-5129
eISSN
1532-2092
D.O.I.
10.1093/europace/eux031
Publisher site
See Article on Publisher Site

Abstract

Abstract Atrial fibrillation (AF) and dementia are both frequent diseases with substantial socioeconomic impact. While AF has been associated with cognitive dysfunction and dementia, we currently lack an exact understanding of the complex association between AF and cognitive decline. Based on an extended literature search we summarize key publications focusing on AF-related cognitive decline and dementia. Moreover, ongoing trials and potential therapeutic implications are discussed. While further prospective studies using a standardized definition of AF and cognitive decline are urgently needed, growing evidence supports the hypothesis that AF is an independent risk factor for cognitive decline and dementia in general and for Alzheimer’s disease in particular. In addition to AF-related ischaemic stroke, white matter damage and systemic inflammation are candidate pathomechanisms and therefore a potential target for prevention of cognitive decline. Whether individualized best-medical therapy of AF holds the promise of preventing cognitive decline should be tested in randomized trials. Atrial fibrillation , Dementia , Alzheimer’s disease , Cognitive decline Introduction It is widely accepted that cerebral health is linked to cardiac health in many ways.1,2 Atrial fibrillation (AF) as well as dementia are frequent diseases, predominantly affecting the elderly. So far, AF is not regarded as independent predictor for dementia, despite of epidemiological similarities and shared (cardiovascular) risk factors. A better understanding of the AF-related risk for dementia might help to tackle these worldwide health problems. This narrative review is based on a literature research in PubMed.gov–last done in May 2016—using the keyword ‘atrial fibrillation’ in various combinations with ‘cognition’, ‘neurocognitive’, ‘cognitive performance/dysfunction/impairment/decline’, ‘Alzheimer’s’ and ‘dementia’ as well as ‘pathophysiology’ and ‘pathomechanism’ with the purpose to outline current knowledge on the relationship of AF and dementia and provide a résumé of explanatory research on the underlying pathomechanisms. Epidemiology of atrial fibrillation and dementia Both AF as well as dementia are frequent diseases—especially in the elderly. Moreover, both are expected to be among the most prominent global epidemiological trends of the 21st century with an overwhelming burden on worldwide health care systems. The number of patients with dementia seems to stabilize in European countries despite population ageing.3 However, the estimated prevalence rates remain substantial in Western Europe: 2600 per 100 000 for those aged 65 years and older, while up to 21 700 per 100 000 for those aged 85 years and above. Women have a 1.5-fold higher life-time risk of developing Alzheimer’s dementia.4 The estimated prevalence rates for AF range from 3700 to 4700 per 100 000 in those aged 60–70 years and from 10 000 to 17 000 per 100 000 for those aged 80 years and older according to a recent review of European data.5 In addition, AF is more prevalent in men, who have a 1.2-fold greater risk of developing AF than women after adjustment for age and predisposing conditions.5 According to the Rotterdam study, the lifetime risk of developing AF by the age of 55 years is 24% in men and 22% in women.6 Given a prevalence of dementia of 2.6% and AF of 3.7%, in theory 6.2% of individuals will be suffering from either one or both diseases, assuming independence of these two conditions. Methodological difficulties in establishing an association of AF with dementia The wide variety of terms used to describe cognitive dysfunction or dementia in clinical studies evaluating the association of AF and dementia renders the interpretation difficult. Terms include: ‘cognitive decline’, ‘cognitive impairment’, ‘low cognitive function’, ‘low cognitive performance’, ‘memory impairment’, ‘visuospatial memory loss’, ‘incident dementia’, ‘dementia without specification’, ‘Alzheimer’s dementia’, and ‘vascular dementia’ amongst others. In addition, a large variety of neuropsychological test batteries is used and often describes cognitive dysfunction in very specific domains. Moreover, accurate diagnosis of dementia is often delayed since the early symptoms often go unnoticed or may be trivialised. Consequently, adequate tools are not used for the diagnosis, likely resulting in insufficient screening for dementia and under-diagnosis in primary care.7 In addition, there is substantial heterogeneity in the diagnosis of dementia according to the commonly used classification schemes (DSM-II, DSM-III-R, DSM-IV, ICD-9 or CAMDEX). In fact, the prevalence of ‘dementia’ in a defined population-based cohort varied from 3.1 to 29.1% merely depending on which definition was used.8 Applying ICD-10 or DSM-IV criteria to the general population will result in 3.1% vs. 9.6% cases of dementia, respectively.9 These apparent discrepancies in diagnostic rates have been described for further diagnostic criteria, i.e. such as proposed by the National Institute on Aging and the Alzheimer’s Association (NIA-AA) or the International Working Group for New Research Criteria for the Diagnosis of Alzheimer’s Disease (IWG).10 Similar difficulties also apply for detection and definition of AF, despite of the fact that ECG-based diagnosis is rather straightforward. About two thirds of AF patients suffer from palpitations, fatigue, dyspnoea or dizziness—so called ‘symptomatic’ AF.11 However, given the often asymptomatic and intermittent nature of AF, the diagnosis of AF is frequently delayed. As an example, a population-based screening among 13 331 individuals aged 75 and 76 years in Sweden detected previously unknown (and therefore untreated) AF in 3% of these individuals using intermittent ECG recordings over 2 weeks.12 Moreover, the definition of AF (i.e. ‘any arrhythmia that has the ECG characteristics of AF and lasts sufficiently long for a 12-lead ECG to be recorded, or at least 30 s on a rhythm strip’ according to Camm et al., (ESC guidelines 2010)13 is based on expert consensus only, namely the ACC/AHA/ESC 2006 guidelines.14 Notably, adaptations of that definition as well as technical advances such as intracardiac monitoring devices or loop recorders resulted in lower (≥ 5 s) or higher bounds (e.g. ≥ 2 min, ≥ 2.5 min, or even 6 min etc.).15 So far, the optimal duration and most cost-effective method of AF detection is a matter of debate, and guideline recommendations remain vague, especially for stroke patients.16–18 Both atrial fibrillation and dementia share the same risk factors Studies evaluating a causal relationship of AF and dementia have to account for overlapping risk factors. Various conditions such as old age, diabetes, chronic kidney disease, sleep apnea, hypertension, heart failure, heavy alcohol consumption, and coronary heart disease are associated with AF as well as dementia,19–31 for further details see Table 1. Table 1 Risk factors associated with atrial fibrillation (AF) as well as dementia or cognitive decline Condition  Author (Enrollment)  Cohort and study design  Cohort characteristics  Methods  Main findings  Diabetes mellitus and dementia  Arvanitakis et al., 200419 (1994–2003)  Catholic nuns, priests, and brothers underwent detailed clinical evaluation. Longitudinal cohort study, United States  n = 824  NINDS- ADRDA Episodic, semantic, working memory, perceptual speed & visuospatial abilities.  Patients with diabetes mellitus had a 65% increase in the risk of developing Alzheimeŕs compared to those without diabetes: HR 1.65 (95% CI 1.10–2.47) after adjusting for age, sex, and educational level.  age 74.4 ± 6.1 (DM) & 75.2 ± 75 (no DM) years, male 44.9% (DM) vs. 28.7% (no DM) follow-up 5.5 years  Diabetes mellitus and AF  Iguchi et al., 200820 (2006)  Non-employed inhabitants of Kurashiki- City, aged >40 years. Community based study, Japan  n = 41 436  ECG  DM was associated with AF in men: OR 1.50 (95% CI 1.15–1.95) and in women: OR 1.40 (95% CI 1.04–1.89) after adjusting for sex, diabetes mellitus, hypercholesterolemia, cardiac disease, chronic kidney disease.  age 76.6 ± 8.5 (AF) years & 71.4 ± 10.5 (no AF) male 50% (AF) & 33% (no AF), no follow-up  Chronic kidney disease and dementia  Hailpern et al., 200721 (1988–1994)  Civilian, noninstitutionalized adults >18 years from the NHANES III Study. Cross-sectional population based study, United States  n = 4849  SDLT, DSST, SRTT  CKD was significantly associated with poor visual attention and learning/concentration OR 2.41 (95% CI 1.30–5.63). Analysis adjusted for age, gender, race, diabetes, and other known potential confounders.  median age 36 years, 49% male, Afro-American 11%, follow-up n.a.  Chronic kidney disease and AF  Liao et al., 201522 (1996–2011)  Patients undergoing renal replacement therapy were compared to patients without CKD or CKD without renal replacement therapy. Retrospective analysis, Taiwan  n = 134 901  ICD-9  Patients with end stage renal disease had a significantly higher risk of new-onset AF: HR 1.28 (95% CI 1.22–1.34) adjusted for age, gender, hypertension, DM, HF, CAD, PAOD, cerebral vascular accident, COPD, cancer & liver cirrhosis.  age 61.7 ± 14.3 years, 49.5% male follow-up 5.1 ± 4.1 years  Sleep apnea and dementia  Spira et al., 200823 (1986–1988)  Community dwelling women aged ≥65 years, Study of Osteoporotic Fractures. Prospective observational study, United States  n = 448  MMSE, Trails B, PSG  All sleep disorder indices were associated with cognitive impairment according to MMSE: OR 3.4 (95% CI 1.4–8.1), adjusted for age, education, and SSRI use.  age 82.8 ± 3.4 years, male 0%, Caucasian 91.5% follow-up 16 years  Sleep apnea and AF  Gami et al. 200724 (1987–2003)  Adult residents of Olmsted county, 1st polysomnography. Retro-spective cohort study, United States  n = 3542  PSG, ECG  Decrease in nocturnal oxygen saturation was a predictor for AF for subjects < 65 years: HR 3.29 (95% CI 1.35–8.04) adjusted for age, male gender, CAD, BMI, nocturnal oxygen saturation.  age 49 ± 14 years, male 66%, follow-up 15 years  Hypertension and cognitive dysfunction  Böhm et al., 201525 (2001–2004)  Patients ≥55 years without heart failure but CAD, PAOD, TIA/stroke or diabetes & organ damage. Data from ONTARGET & TRANSCEND.  n = 24 593  MMSE  SBP-CV (OR1.32 (95% CI 1.10–1.58)) and mean heart rate (OR 1.40 (95% CI 1.18–1.66)) were associated with cognitive decline after adjusting for a large variety of factors (incl. MMST baseline).  mean age 66 years, male 72.5%, Caucasian 74%, follow up 56 months  Hypertension and AF  Tremblay-Gravel et al., 201526 (1999–2008)  Patients ≥65 years or LVEF ≤35% or NYHA class II–IV symptoms. Pooled data from AFFIRM & AF-CHF.  n = 2715  ECG  AF recurrence after cardioversion was higher in patients with SBP with >140 mmHg. HR 1.47 (95% CI 1.12–1.93) adjusted for BMI, AF duration, rhythm at baseline, left atrial dimension, anticoagulant use, calcium channel blocker use.  mean age 68 ± 8 years, male 66%, follow up 3.5 years  Heart failure and dementia  Qiu et al., 200627 (1987)  All registered inhabitants of Kungsholmen district of Stockholm, ≥ 75years. Community-based cohort study, Sweden  n = 1301  DSM-III, MMSE  Heart failure is associated with dementia and Alzheimer disease: HR 1.84 (95% CI 1.35–2.51) adjusted for age, sex, education, baseline MMSE, stroke, diabetes mellitus, antihypertensives, blood pressure, pulse, BMI, and survival status.  age 83.3 ± 5.4 (HF) & 81.2 ± 4.8 (non HF), male 20% (HF) & 23.9% (non HF), follow-up 5 years  Heart failure or coronary heart disease and AF  Benjamin et al., 199428 (1948)  Cohort of the Framingham study, subjects restricted 55–94 years. Population-based estimates, United States  n = 4731  ECG  HF associated with risk of AF in men: OR 4.5 (95% CI 3.1–6.6) & women: OR 5.9 (95% CI 4.2–8.4); CHD associated with AF in men: 1.4 (95% CI 1.0–2.0) & women: 1.2 (95% CI 0.8–1.8) adjusted for age, diabetes, HT, valvular heart disease.  mean age women 75 & men 72%; male 44% follow-up 38 years  Coronary heart disease and cognitive impairment  Roberts et al., 201029 (2004)  Incidence of amnestic and non-amnestic mild cognitive impairment in Olmsted County. Population-based longitudinal cohort study, United States  n = 1969  Dementia Rating Scale, testing of memory, executive function, language, visuospatial skills.  CHD associated with mild cognitive impairment: OR 1.85 (95% CI 1.12–3.05) but not with amnestic. Analysis adjusted for age, sex, education, DM, HT, stroke, BMI, depression, dyslipidaemia, ApoE genotype.  mean age 80.4 years, male 50.9%, Caucasian 98%, follow-up n.a.  Heavy alcohol consumption and dementia  Mukamal et al., 200330 (1989–1993)  Cardiovascular Health Study aged ≥65years, independent, randomly selected from Medicare. Population-based cohort study, United States  n = 5888  DSM-IV, 3MSE, MMSE, modified MMSE and MRI, DSST, IQCODE  Heavy alcohol consumption associated with dementia: OR 1.22 (95% CI 0.60–2.49) adjusted for age, sex, race, ApoE4, education, income, oestrogen replacement therapy, smoking, diabetes, BMI, cholesterol, AF, CHF, stroke/TIA.  mean age 78 years, male ∼41%, Afro-American ∼10%, follow-up 6 years  Heavy alcohol consumption and AF  Mukamal et al., 200531 (1976, 1981)  Randomly chosen participants from the Copenhagen Population Register. Population-based cohort study, Denmark  n = 16 415  ECG  Heavy alcohol consumption associated with AF: HR 1.45 (95% CI 1.02–2.04) adjusted for age, smoking, education, cohabitation, history of CVD, diabetes, income, physical activity, BMI, height.  median age 55.8 (men) & 56.8 (women), male 46,%, follow-up 15 years  Condition  Author (Enrollment)  Cohort and study design  Cohort characteristics  Methods  Main findings  Diabetes mellitus and dementia  Arvanitakis et al., 200419 (1994–2003)  Catholic nuns, priests, and brothers underwent detailed clinical evaluation. Longitudinal cohort study, United States  n = 824  NINDS- ADRDA Episodic, semantic, working memory, perceptual speed & visuospatial abilities.  Patients with diabetes mellitus had a 65% increase in the risk of developing Alzheimeŕs compared to those without diabetes: HR 1.65 (95% CI 1.10–2.47) after adjusting for age, sex, and educational level.  age 74.4 ± 6.1 (DM) & 75.2 ± 75 (no DM) years, male 44.9% (DM) vs. 28.7% (no DM) follow-up 5.5 years  Diabetes mellitus and AF  Iguchi et al., 200820 (2006)  Non-employed inhabitants of Kurashiki- City, aged >40 years. Community based study, Japan  n = 41 436  ECG  DM was associated with AF in men: OR 1.50 (95% CI 1.15–1.95) and in women: OR 1.40 (95% CI 1.04–1.89) after adjusting for sex, diabetes mellitus, hypercholesterolemia, cardiac disease, chronic kidney disease.  age 76.6 ± 8.5 (AF) years & 71.4 ± 10.5 (no AF) male 50% (AF) & 33% (no AF), no follow-up  Chronic kidney disease and dementia  Hailpern et al., 200721 (1988–1994)  Civilian, noninstitutionalized adults >18 years from the NHANES III Study. Cross-sectional population based study, United States  n = 4849  SDLT, DSST, SRTT  CKD was significantly associated with poor visual attention and learning/concentration OR 2.41 (95% CI 1.30–5.63). Analysis adjusted for age, gender, race, diabetes, and other known potential confounders.  median age 36 years, 49% male, Afro-American 11%, follow-up n.a.  Chronic kidney disease and AF  Liao et al., 201522 (1996–2011)  Patients undergoing renal replacement therapy were compared to patients without CKD or CKD without renal replacement therapy. Retrospective analysis, Taiwan  n = 134 901  ICD-9  Patients with end stage renal disease had a significantly higher risk of new-onset AF: HR 1.28 (95% CI 1.22–1.34) adjusted for age, gender, hypertension, DM, HF, CAD, PAOD, cerebral vascular accident, COPD, cancer & liver cirrhosis.  age 61.7 ± 14.3 years, 49.5% male follow-up 5.1 ± 4.1 years  Sleep apnea and dementia  Spira et al., 200823 (1986–1988)  Community dwelling women aged ≥65 years, Study of Osteoporotic Fractures. Prospective observational study, United States  n = 448  MMSE, Trails B, PSG  All sleep disorder indices were associated with cognitive impairment according to MMSE: OR 3.4 (95% CI 1.4–8.1), adjusted for age, education, and SSRI use.  age 82.8 ± 3.4 years, male 0%, Caucasian 91.5% follow-up 16 years  Sleep apnea and AF  Gami et al. 200724 (1987–2003)  Adult residents of Olmsted county, 1st polysomnography. Retro-spective cohort study, United States  n = 3542  PSG, ECG  Decrease in nocturnal oxygen saturation was a predictor for AF for subjects < 65 years: HR 3.29 (95% CI 1.35–8.04) adjusted for age, male gender, CAD, BMI, nocturnal oxygen saturation.  age 49 ± 14 years, male 66%, follow-up 15 years  Hypertension and cognitive dysfunction  Böhm et al., 201525 (2001–2004)  Patients ≥55 years without heart failure but CAD, PAOD, TIA/stroke or diabetes & organ damage. Data from ONTARGET & TRANSCEND.  n = 24 593  MMSE  SBP-CV (OR1.32 (95% CI 1.10–1.58)) and mean heart rate (OR 1.40 (95% CI 1.18–1.66)) were associated with cognitive decline after adjusting for a large variety of factors (incl. MMST baseline).  mean age 66 years, male 72.5%, Caucasian 74%, follow up 56 months  Hypertension and AF  Tremblay-Gravel et al., 201526 (1999–2008)  Patients ≥65 years or LVEF ≤35% or NYHA class II–IV symptoms. Pooled data from AFFIRM & AF-CHF.  n = 2715  ECG  AF recurrence after cardioversion was higher in patients with SBP with >140 mmHg. HR 1.47 (95% CI 1.12–1.93) adjusted for BMI, AF duration, rhythm at baseline, left atrial dimension, anticoagulant use, calcium channel blocker use.  mean age 68 ± 8 years, male 66%, follow up 3.5 years  Heart failure and dementia  Qiu et al., 200627 (1987)  All registered inhabitants of Kungsholmen district of Stockholm, ≥ 75years. Community-based cohort study, Sweden  n = 1301  DSM-III, MMSE  Heart failure is associated with dementia and Alzheimer disease: HR 1.84 (95% CI 1.35–2.51) adjusted for age, sex, education, baseline MMSE, stroke, diabetes mellitus, antihypertensives, blood pressure, pulse, BMI, and survival status.  age 83.3 ± 5.4 (HF) & 81.2 ± 4.8 (non HF), male 20% (HF) & 23.9% (non HF), follow-up 5 years  Heart failure or coronary heart disease and AF  Benjamin et al., 199428 (1948)  Cohort of the Framingham study, subjects restricted 55–94 years. Population-based estimates, United States  n = 4731  ECG  HF associated with risk of AF in men: OR 4.5 (95% CI 3.1–6.6) & women: OR 5.9 (95% CI 4.2–8.4); CHD associated with AF in men: 1.4 (95% CI 1.0–2.0) & women: 1.2 (95% CI 0.8–1.8) adjusted for age, diabetes, HT, valvular heart disease.  mean age women 75 & men 72%; male 44% follow-up 38 years  Coronary heart disease and cognitive impairment  Roberts et al., 201029 (2004)  Incidence of amnestic and non-amnestic mild cognitive impairment in Olmsted County. Population-based longitudinal cohort study, United States  n = 1969  Dementia Rating Scale, testing of memory, executive function, language, visuospatial skills.  CHD associated with mild cognitive impairment: OR 1.85 (95% CI 1.12–3.05) but not with amnestic. Analysis adjusted for age, sex, education, DM, HT, stroke, BMI, depression, dyslipidaemia, ApoE genotype.  mean age 80.4 years, male 50.9%, Caucasian 98%, follow-up n.a.  Heavy alcohol consumption and dementia  Mukamal et al., 200330 (1989–1993)  Cardiovascular Health Study aged ≥65years, independent, randomly selected from Medicare. Population-based cohort study, United States  n = 5888  DSM-IV, 3MSE, MMSE, modified MMSE and MRI, DSST, IQCODE  Heavy alcohol consumption associated with dementia: OR 1.22 (95% CI 0.60–2.49) adjusted for age, sex, race, ApoE4, education, income, oestrogen replacement therapy, smoking, diabetes, BMI, cholesterol, AF, CHF, stroke/TIA.  mean age 78 years, male ∼41%, Afro-American ∼10%, follow-up 6 years  Heavy alcohol consumption and AF  Mukamal et al., 200531 (1976, 1981)  Randomly chosen participants from the Copenhagen Population Register. Population-based cohort study, Denmark  n = 16 415  ECG  Heavy alcohol consumption associated with AF: HR 1.45 (95% CI 1.02–2.04) adjusted for age, smoking, education, cohabitation, history of CVD, diabetes, income, physical activity, BMI, height.  median age 55.8 (men) & 56.8 (women), male 46,%, follow-up 15 years  NINDS-ADRDA, National Institute of Neurological Disorders and Stroke and Alzheimer’s disease and related disorders association; MMSE, Mini-Mental State Examination; SDLT, Serial Digit Learning Test; DSST, Digit Symbol Substitution Test, SRTT, Simple Reaction Time Test; Trails B, Trail Making Test Part B; IQCODE, Informant Questionnaire on the cognitive decline of the Elderly; PSG, Polysomnography; HTN, Hypertension; HF, heart failure; CAD, coronary artery disease; PAOD, peripheral arterial occlusive disease; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; SBP-CV, Systolic blood-pressure coefficient of variation; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; GFR, Glomerular Filtration Rate; BMI, Body Mass Index; SSRI, selective serotonin reuptake inhibitor; NHANES, National Health and Nutrition Examination Survey. AF is a risk factor for cognitive decline and dementia—candidate pathomechanisms A number of prospective studies demonstrated an association between AF and cognitive decline or dementia (Table 2;32–38). As an example, the combined post-hoc analysis of two prospective multicenter trials demonstrated that AF was associated with an increased risk of cognitive decline [HR 1.14 (95% CI 1.03–1.26)], dementia [HR 1.30 (95% CI 1.14–1.49)] as well as loss of independence in performing activities of daily living [HR 1.35 (95% CI 1.19–1.54)].36 The Cardiovascular Health Study reported a faster cognitive decline in patients who developed AF within the next 7 years.37 In addition, the prospective Intermountain Heart Collaborative Study demonstrated a significantly increased risk of dementia in AF patients [HR 1.36 (95% CI 1.1–1.6)].35 A similar association was found for AF and Alzheimer’s dementia (AD), and the relative risk (RR) was significantly higher in AF patients aged <70 years with no apparent association in older AF patients. However, a major limitation of these studies is missing serial brain imaging for covert strokes or white matter hyperintensities. Table 2 Studies assessing an association between atrial fibrillation (AF) and dementia or cognitive decline Author (Enrollment)  Cohort and study design  Cohort characteristics  Methods  Main findings  Ott et al., 199732 (1989)  Inhabitants of Rotterdam with dementia compared to subjects without dementia regarding the presence of AF. Population based prospective cohort study, Netherlands  n = 6584  AF: 12-lead ECG, Cognition: DSM-IIIR, MMSE, NINDS-ADRDA, NINDS-AIREN  Dementia was more than twice as common in subjects with AF without history of stroke (<75 years): OR 2.6 (95% CI 0.6–11.4) adjusted for age, sex, and stroke history.  age 69.2 ± 9.1 years, male 41.8%  Elias et al., 200633 (1971)  Men with a history of AF compared to men without AF. Community based sample, United States  n = 1011  AF: 12-lead ECG or Holter. Cognition: DSM-IV, NINDS-ADRDA, Wechsler scales, Trail-making A+B  AF in stroke-free men was associated with lower performance in global cognitive ability and cognitive abilities: HR 4.0 (95% CI 1.8- 8.7) adjusted for age, education, multiple cardiovascular risk factors, and cardiovascular disease.  age 60.5 ± 9.4 (noAF) & 68.1 ± 7.0 (AF), male 100% follow-up 30 years  Knecht et al., 200834 (2004–2007)  AF patients without stroke according to brain imaging compared to non-AF subjects. Cohort based -community controlled MRI study, Germany  n = 533  AF: 12-lead ECG. Cognition: STroop-Test, DSST, Trail A+B, digit span, Rey Osterrieth complex figure test  AF was independently related to lower hippocampal volume (p < 0.01), total brain volume (p < 0.01) and lower cognitive performance in learning and memory (ß=-0.115, SE 0.115, p < 0.01) and attention and executive functions (ß=0.105, SE -0.109, p < 0.01). Analysis adjusted for age, gender, education, systolic blood pressure, BMI, HT, diabetes, dyslipoproteinemia, smoking, CAD, medication.  age 64 ± 7 (noAF) & 60 ± 12 (AF); male 43.8% (no AF) & 83.8% (AF)  Bunch et al., 201035 (1994)  Patients diagnosed with any type of heart disease from the Intermountain Healthcare system. Prospective cohort study, United Sates  n = 10 161  AF: ICD-9 codes, ECG-database. Cognition: ICD-9  AF was an independent risk for dementia, all subtypes (senile, vascular, Alzheimeŕs and non-specified dementia) and faster cognitive decline. For Alzheimeŕs <70 years: OR 2.30 (p < 0.01) multivariable-adjusted age-based analysis.  age 60.6 ± 17.9 years, male 60%, white 89%, follow-up 5 years  Marzona et al., 201236 (2001–2004)  Patients aged >55 years with cardiovascular disease or diabetes an end-organ damage. Post-hoc analysis of ONTARGET & TRANSCEND.  n = 31 506  AF: 12-lead ECG. Cognition: MMSE  AF was associated with risk of dementia HR 1.30 (95% CI 1.14- 1.49) adjusted for age, education, sex, baseline MMSE, SBP, stroke/TIA, HT, diabetes, albuminuria, MI, creatinine, medication, smoking, BMI, physical activity, sleep apnea, alcohol consumption.  age 66.5 ± 7.2 years, male 71.3%, follow-up 56 months  Thacker et al., 201337 (1989–1993)  Cognition in AF patients compared to non-AF patients without prior stroke, aged >65 years. Community-based prospective study, United States  n = 5150  AF: 12-lead ECG, Cognition: 3MSE DSST  In the group of 75 year old subjects, compared to non-AF patients, AF patients showed faster cognitive decline in the absence of overt stroke with a decline of -3.0 points (95% CI -4.1- -1.8) in 3MSE scores over the following 5 years. Analysis adjusted for age, sex, race, education, cigarette smoking, alcohol use, diabetes, HT, blood pressure, CAD, HF, and the interaction of age.  mean age 73.0 ± 5.4 years, male 41.2% follow-up 7 years  deBrujin et al., 201538 (1989)  Association of AF with incident dementia in people > 55 years. Population based prospective cohort study, Netherlands  n = 6514  AF: 12-lead ECG, Cognition: 3MSE, GMSS, CAMDEX-R  Incident AF was associated with risk of dementia in participants <67 years: HR 1.81 (95% CI 1.11- 2.94) adjusted for age, sex, diabetes mellitus, smoking, total cholesterol and HDL, lipid-lowering medication, BP, BP lowering medication, educational level, ever use of oral anticoagulation, CAD, HF, ApoE4.  age 68.3 ± 8.5 (no AF) & 75.7 ± 8.1 (AF), male 41.6% (no AF) & 49.4% (AF), follow-up 20 years  Author (Enrollment)  Cohort and study design  Cohort characteristics  Methods  Main findings  Ott et al., 199732 (1989)  Inhabitants of Rotterdam with dementia compared to subjects without dementia regarding the presence of AF. Population based prospective cohort study, Netherlands  n = 6584  AF: 12-lead ECG, Cognition: DSM-IIIR, MMSE, NINDS-ADRDA, NINDS-AIREN  Dementia was more than twice as common in subjects with AF without history of stroke (<75 years): OR 2.6 (95% CI 0.6–11.4) adjusted for age, sex, and stroke history.  age 69.2 ± 9.1 years, male 41.8%  Elias et al., 200633 (1971)  Men with a history of AF compared to men without AF. Community based sample, United States  n = 1011  AF: 12-lead ECG or Holter. Cognition: DSM-IV, NINDS-ADRDA, Wechsler scales, Trail-making A+B  AF in stroke-free men was associated with lower performance in global cognitive ability and cognitive abilities: HR 4.0 (95% CI 1.8- 8.7) adjusted for age, education, multiple cardiovascular risk factors, and cardiovascular disease.  age 60.5 ± 9.4 (noAF) & 68.1 ± 7.0 (AF), male 100% follow-up 30 years  Knecht et al., 200834 (2004–2007)  AF patients without stroke according to brain imaging compared to non-AF subjects. Cohort based -community controlled MRI study, Germany  n = 533  AF: 12-lead ECG. Cognition: STroop-Test, DSST, Trail A+B, digit span, Rey Osterrieth complex figure test  AF was independently related to lower hippocampal volume (p < 0.01), total brain volume (p < 0.01) and lower cognitive performance in learning and memory (ß=-0.115, SE 0.115, p < 0.01) and attention and executive functions (ß=0.105, SE -0.109, p < 0.01). Analysis adjusted for age, gender, education, systolic blood pressure, BMI, HT, diabetes, dyslipoproteinemia, smoking, CAD, medication.  age 64 ± 7 (noAF) & 60 ± 12 (AF); male 43.8% (no AF) & 83.8% (AF)  Bunch et al., 201035 (1994)  Patients diagnosed with any type of heart disease from the Intermountain Healthcare system. Prospective cohort study, United Sates  n = 10 161  AF: ICD-9 codes, ECG-database. Cognition: ICD-9  AF was an independent risk for dementia, all subtypes (senile, vascular, Alzheimeŕs and non-specified dementia) and faster cognitive decline. For Alzheimeŕs <70 years: OR 2.30 (p < 0.01) multivariable-adjusted age-based analysis.  age 60.6 ± 17.9 years, male 60%, white 89%, follow-up 5 years  Marzona et al., 201236 (2001–2004)  Patients aged >55 years with cardiovascular disease or diabetes an end-organ damage. Post-hoc analysis of ONTARGET & TRANSCEND.  n = 31 506  AF: 12-lead ECG. Cognition: MMSE  AF was associated with risk of dementia HR 1.30 (95% CI 1.14- 1.49) adjusted for age, education, sex, baseline MMSE, SBP, stroke/TIA, HT, diabetes, albuminuria, MI, creatinine, medication, smoking, BMI, physical activity, sleep apnea, alcohol consumption.  age 66.5 ± 7.2 years, male 71.3%, follow-up 56 months  Thacker et al., 201337 (1989–1993)  Cognition in AF patients compared to non-AF patients without prior stroke, aged >65 years. Community-based prospective study, United States  n = 5150  AF: 12-lead ECG, Cognition: 3MSE DSST  In the group of 75 year old subjects, compared to non-AF patients, AF patients showed faster cognitive decline in the absence of overt stroke with a decline of -3.0 points (95% CI -4.1- -1.8) in 3MSE scores over the following 5 years. Analysis adjusted for age, sex, race, education, cigarette smoking, alcohol use, diabetes, HT, blood pressure, CAD, HF, and the interaction of age.  mean age 73.0 ± 5.4 years, male 41.2% follow-up 7 years  deBrujin et al., 201538 (1989)  Association of AF with incident dementia in people > 55 years. Population based prospective cohort study, Netherlands  n = 6514  AF: 12-lead ECG, Cognition: 3MSE, GMSS, CAMDEX-R  Incident AF was associated with risk of dementia in participants <67 years: HR 1.81 (95% CI 1.11- 2.94) adjusted for age, sex, diabetes mellitus, smoking, total cholesterol and HDL, lipid-lowering medication, BP, BP lowering medication, educational level, ever use of oral anticoagulation, CAD, HF, ApoE4.  age 68.3 ± 8.5 (no AF) & 75.7 ± 8.1 (AF), male 41.6% (no AF) & 49.4% (AF), follow-up 20 years  MMSE, Modified Mini-Mental State Examination; DSST, Digit Symbol Substitution Test; GMSS, Geriatric Mental State Schedule; CAMDEX-R, Cambridge Examination for Mental Disorders of the Elderly; NINDS-ADRDA, National Institute of Neurological Disorders and Alzheimer’s Disease and Related Disorders; NINDS-AIREN, Association Internationale pour la Recherche et l'Enseignement en Neurosciences; HTN, hypertension; BMI, Body Mass Index; CAD, coronary artery disease; ACE, angiotensin-converting enzyme; TIA, transient ischaemic attack; HF, heart failure. A systematic review by Santangeli et al.39 comprised eight prospective studies including more than 77 000 patients of whom 11 700 (17%) had AF.33,35,36,40–44 The authors evaluated the association between AF and the incidence of dementia in patients not suffering an acute stroke and with normal cognitive function at baseline. After adjusting for confounders, an independent risk of incident dementia was demonstrated in AF patients with a HR 1.4 (95% CI 1.2–1.7). An even larger systematic review published in 2013 by Kalantarian assessed the association of AF with cognitive decline or dementia. Including prospective and non-prospective studies, mainly using MMSE and DSM-III or IV criteria, the risk for cognitive impairment was more than doubled in AF patients with a history of stroke [RR 2.70 (95% CI 1.82–4.00)]. In addition, there was a significantly increased risk for cognitive decline in patients with or without a history of stroke [RR 1.40 (95% CI 1.19–1.64)], as well as in AF patients without a history of stroke [RR 1.37 (95% CI 1.08–1.73)].45 AF-related ischaemic stroke causes cognitive decline AF is associated with a four- to five-fold risk of ischaemic stroke, and at least 15% of all strokes are related to AF.11,15 The fact that ischaemic strokes may cause cognitive decline is widely accepted and part of the etiological concept of ‘post-stroke’, and ‘vascular’ dementia.46,47 New-onset dementia was reported in up to 33% of all stroke patients within 5 years.47 In addition to manifest (or ‘overt’) ischaemic stroke, so called clinically ‘silent’ or ‘covert’ strokes contribute to cognitive decline.48,49 Silent brain infarction is common in the general population (7–28%) and can be found in 28–90% of AF patients. Moreover, AF was significantly associated with silent brain infarction in six cohort studies or case series, with odds ratios (ORs) ranging from 2.2 to 7.2.50 AF may cause cognitive dysfunction independent of ischaemic stroke Several prospective studies and two meta-analyses39,45 postulated an increased risk of dementia in AF-patients independent from AF-related (clinically overt) ischaemic stroke32–38 (see Table 2). Unfortunately, in the majority of studies investigating the association of AF and cognitive decline or dementia, no brain imaging was performed to estimate the potential impact of clinically ‘silent’ strokes.32,33,35–38 However, there is growing evidence demonstrating a potential role of cerebral hypoperfusion, chronic inflammation, as well as endothelial dysfunction in dementia,47 and similar mechanisms may be involved in AF-related cognitive decline. Another piece of evidence comes from a case control study in Germany, postulating that AF alters cognitive function independent of stroke.34 The authors assessed memory function (i.e. by using a detailed test battery for cognitive function) and measured hippocampal volumes (by MRI) in stroke-free patients with (n = 87) or without atrial fibrillation (n = 446). AF patients included in this study were relatively young (mean age 60 years). Presence of AF was independently related to poor performance in learning and memory, as well as attention and executive functions. In addition, smaller hippocampal volumes were found in AF patients. Somewhat surprisingly, the authors hypothesised that hippocampal atrophy may relate to microembolism at an early stage that might affect the entire cerebral tissue.34 However, in our opinion, this assumption can be challenged because brain MRI did not demonstrate white matter temporal hyperintensities in these patients. AF-related hypoperfusion of the brain – the ‘CATCH’ hypothesis An AF-related reduction of cardiac output (through beat-to-beat-variability and subsequent reduced left-ventricular output) may lead to chronic hypoperfusion of the brain and hypoxia, as similarly reported for heart failure (see Figure 1).27,51–54 As an example, the Framingham Offspring Study evaluated the association between heart failure-related cerebral hypoperfusion and cognitive decline in 1114 patients by using differentiated neuropsychological testing and brain MRI. Comparing left ventricular ejection fraction (LVEF) quintiles, the lowest LVEF was associated with poorer cognitive performance.53 In addition, even subclinical diastolic dysfunction has been linked to dementia.54 A transcranial Doppler study including 187 heart failure patients (minimum NYHA II) associated cognitive performance with cerebral blood flow velocity. The study demonstrates significantly lower cerebral blood flow velocity in heart failure patients with AF, compared to heart failure patients without AF, associated with worse performance in some cognitive domains.55 Figure 1 View largeDownload slide Candidate pathophysiologic mechanisms of atrial fibrillation-related cognitive decline and dementia. Figure 1 View largeDownload slide Candidate pathophysiologic mechanisms of atrial fibrillation-related cognitive decline and dementia. Based on an animal model of cerebral hypoperfusion demonstrating that hypoperfusion leads to chronic suboptimal delivery of nutrients and reduced clearance of amyloid-beta and other toxins, de la Torre formulated the CATCH hypothesis (ie., critically attained threshold of cerebral hypoperfusion).56,57 However, in our view this hypothesis cannot explain the majority of dementias because cerebral autoregulation is expected to maintain cerebral blood flow during a wide blood pressure range and evidence is lacking that cerebral autoregulation is dysfunctional in the majority of AF-patients.58 Even in patients with disturbed cerebral autoregulation, a critical dysregulation of blood pressure would be needed to have an impact on brain perfusion. That is not the case in the majority of AF patients, since AF may reduce (preserved) cardiac ejection fraction by only about one fifth.59 Nevertheless, AF is an independent risk factor for (chronic) heart failure, and about 30% of all AF patients suffer from (chronic) heart failure with reduced ejection fraction.60 AF-related systemic inflammation Two comprehensive overviews of available case-control studies and prospective cohort studies summarise potential mechanisms linking initiation and perpetuation of AF to systemic inflammation, mediated by CRP, interleukin (IL) IL-2, IL-6, and IL-8, tumor necrosis factor-alpha (TNF-α) or monocyte-chemoattractant protein-161,62 amongst others. Furthermore, there is growing evidence that AF itself induces the release of CRP and inflammatory cytokines, in turn leading to platelet activation. As shown in case-series including AF patients undergoing left atrial catheter ablation,63,64 highly-sensitive-CRP (hs-CRP) levels and IL-6 levels were reduced after restoration of sinus rhythm. In addition, AF also induces endothelial dysfunction and is associated with increased coagulation activity, as indicated by higher levels of D-dimer, fibrinogen, prothrombin fragment 1 and 2, platelet factor-4, thromboglobulin, and von Willebrand factor.61,65,66 AF-induced chronic inflammation may cause cognitive decline via malfunctioning of cerebrovascular regulation, which has been linked to Alzheimer’s and vascular dementia.67,68 In a cohort study of 370 patients with persistent or permanent non-valvular AF, TNF-α baseline blood-levels were a significant predictor of ischaemic stroke during a follow-up of 3 years.69 Animal research on the sphingosine-1-phosphate (S1P) signaling pathway has recently shed more light on the potential relationship of inflammation and dementia: S1P signaling has emerged as an important pathway with vasoconstrictive effects on cerebral arteries. Factors modulating the sphingosine kinase 1 (Sphk 1) activity—the core element of this pathway—alter myogenic response in smooth muscle cells and in turn might contribute to critical hypoperfusion of the brain.70,71 TNF-α is a well-described activator of Sphk1, which phosphorylates sphingosine to sphingosine-1-phosphate (SP1) and has become a hallmark of cerebrovascular72 and cardiovascular73 disease. The pro-constrictive effects of S1P are mediated via the S1P2 receptor, which activates RhoA/Rho-kinase and ultimately inhibits myosin light chain phosphatase, which leads to a higher sensitivity to intracellular calcium. In an animal model, the application of TNF-α antagonist etanercept induced a reversion of TNF-α/sphingosine-1-phospahte mediated cerebral vasoconstriction.71,74 While this finding may point to potential novel treatment targets, these data are still lacking confirmation from large prospective studies in humans. Does treatment of AF or stroke prevention in AF patients prevent cognitive decline? Anticoagulation Effective oral anticoagulation reduces the burden of AF-related embolic strokes in patients with additional stroke risk factors and is strongly recommended by current guidelines.11 Therefore, it is plausible to assume that effective anticoagulation of AF-patients should also lead to preserved cognitive function. In support of this notion, it was demonstrated that a low time in the therapeutic range in warfarin treated AF patients significantly increased the risk of incident dementia.75 Furthermore, the comparison of warfarin treated AF patients and warfarin treated non-AF patients showed that AF patients had a higher risk for dementia than warfarin treated patients for other reasons,76 further underlining the impact of AF on cognition independent from stroke (for more details see Table 3,75–82). Nevertheless, until now there is no convincing prospective evidence that effective oral anticoagulation may prevent dementia in AF patients82 and large studies with longer follow up are needed to clarify the impact of anticoagulation on cognition, as described below. Table 3 Impact of oral anticoagulation75,76,79–82 as well as rate- or rhythm control77,78 on cognitive function in AF patients Author (Enrollment)  Cohort and study design  Cohort characteristics  Definition of dementia  Main findings  Chung et al. 200575 (1995–1999)  Cognition in rate vs. rhythm control in AF patients enrolled in AFFIRM.United States/Canada.  n = 245,  MMSE  No significant difference of MMSE in AF patients randomized to rhythm or rate control in the adjusted analysis (but no risk ratios provided in the publication).  age 69.7 ± 9, male 61%, follow-up 5 years  Bunch et al., 201176 (1994)  Impact of catheter ablation for AF on long-term risk of dementia. Cohort study based on a database, United States.  n = 37 908  ICD-9  Ablated patients had a significantly lower risk of dementia compared to AF patients without ablation: HR 2.81 (95% CI not provided; p < 0.001) adjusted for age, sex, diabetes, HTN, hyperlipidemia, CHF, renal failure, TIA history, CVA, MI.  age 66.0 ± 13.3 years, male 60.8%, Caucasian 89%, follow up 3 years  Jacobs et al., 201477 (1994)  Incidence of dementia in warfarin-treated AF patients with low vs. high time in the therapeutic range. Retrospective population-based study, United States  n = 2605  ICD-9  Low time in the therapeutic range increases the risk of incident dementia HR 5.34 (CI 95% 2–12) adjusted for age, sex, HTN, hyperlipidemia, diabetes mellitus, smoking, CHF, CAD, coronary bypass, myocardial infarction, renal failure.  age 73.7 ± 10.8 years, male 54%, follow-up 4 years  Mavaddat et al., 201478 (2001–2004)  Cognitive function in the Birmingham Atrial Fibrillation Treatment of the Aged Study. Prospective randomized open – label trial, United Kingdom  n = 973  MMSE  Not significantly improved cognition in warfarin-treated AF patients at the end of follow- up. Adjusted analysis for baseline short orientation-memory concentration test, age, sex, and previous stroke or TIA.  age 81.5 ± 4.3 years, male 55%, follow-up 33 months  Jacobs et al., 201679 (2010–2014)  Incidence of dementia in NOAC vs. warfarin users because of AF, thrombosis or valvular heart disease. Retrospective population-based study, United States  n = 5254  ICD-9, ICD-10  NOAC patients had a lower risk of dementia/stroke/TIA compared with warfarin-treated patients: HR 0.49 (95% CI 0.35–0.69) adjusted for age, sex, HTN, hyperlipidemia, diabetes mellitus, CHF, CAD, coronary bypass, stroke/TIA.  age 72.4 ± 10.9 years, male 59%, follow-up warfarin 309 days, NOACs 185 days  Bo et al., 201680 (2010–2013)  Effects of anticoagulation on AF patients aged ≥65 years, discharged from geriatric ward. Retrospective cohort study, Italy  n = 980  SPMSQ  Anticoagulation was associated with reduced mortality and better cognitive status: OR 2.29 (95% CI 1.47–3.57) adjusted for age, sex, congestive heart failure; HTN; aged≥75 years, diabetes, stroke, systemic embolism, vascular disease, abnormal renal/liver function, bleeding history, labile INR, drugs/alcohol.  age 83.4 ± 6.7 years, male 40%, follow-up 571 days  Bunch et al., 201681 (1994)  Prevalence of dementia in warfarin treated AF-patients and warfarin treated non-AF patients. Retrospective cohort study, United States  n = 10 537  ICD-9 + ICD-10  Warfarin treated AF patients with had a higher risk for dementia than warfarin treated non-AF patients HR = 2.42 (95% CI 1.85–3.18) adjusted analysis for age, sex, HTN, hyperlipidemia, diabetes, smoking, CHF, stroke, TIA, CAD, renal failure, prior CABG, PCI, bleed, malignancy, fall, and sleep apnea.  age 69.3 ± 10.9 years, male 52%, follow-up 2021 days  Moffitt et al., 201682 (studies from 1998–2015)  Meta-analysis of randomized controlled trials regarding cognition or dementia in patients with AF or atrial flutter.  n = 15876  MMSE  Potential benefit of anticoagulation in comparison to controls with antiplatelet therapy in patients with AF (or atrial flutter) over time, but no definitive evidence of cognitive benefit from anticoagulation treatment.  age/men n.a., follow-up 5.9 years  Author (Enrollment)  Cohort and study design  Cohort characteristics  Definition of dementia  Main findings  Chung et al. 200575 (1995–1999)  Cognition in rate vs. rhythm control in AF patients enrolled in AFFIRM.United States/Canada.  n = 245,  MMSE  No significant difference of MMSE in AF patients randomized to rhythm or rate control in the adjusted analysis (but no risk ratios provided in the publication).  age 69.7 ± 9, male 61%, follow-up 5 years  Bunch et al., 201176 (1994)  Impact of catheter ablation for AF on long-term risk of dementia. Cohort study based on a database, United States.  n = 37 908  ICD-9  Ablated patients had a significantly lower risk of dementia compared to AF patients without ablation: HR 2.81 (95% CI not provided; p < 0.001) adjusted for age, sex, diabetes, HTN, hyperlipidemia, CHF, renal failure, TIA history, CVA, MI.  age 66.0 ± 13.3 years, male 60.8%, Caucasian 89%, follow up 3 years  Jacobs et al., 201477 (1994)  Incidence of dementia in warfarin-treated AF patients with low vs. high time in the therapeutic range. Retrospective population-based study, United States  n = 2605  ICD-9  Low time in the therapeutic range increases the risk of incident dementia HR 5.34 (CI 95% 2–12) adjusted for age, sex, HTN, hyperlipidemia, diabetes mellitus, smoking, CHF, CAD, coronary bypass, myocardial infarction, renal failure.  age 73.7 ± 10.8 years, male 54%, follow-up 4 years  Mavaddat et al., 201478 (2001–2004)  Cognitive function in the Birmingham Atrial Fibrillation Treatment of the Aged Study. Prospective randomized open – label trial, United Kingdom  n = 973  MMSE  Not significantly improved cognition in warfarin-treated AF patients at the end of follow- up. Adjusted analysis for baseline short orientation-memory concentration test, age, sex, and previous stroke or TIA.  age 81.5 ± 4.3 years, male 55%, follow-up 33 months  Jacobs et al., 201679 (2010–2014)  Incidence of dementia in NOAC vs. warfarin users because of AF, thrombosis or valvular heart disease. Retrospective population-based study, United States  n = 5254  ICD-9, ICD-10  NOAC patients had a lower risk of dementia/stroke/TIA compared with warfarin-treated patients: HR 0.49 (95% CI 0.35–0.69) adjusted for age, sex, HTN, hyperlipidemia, diabetes mellitus, CHF, CAD, coronary bypass, stroke/TIA.  age 72.4 ± 10.9 years, male 59%, follow-up warfarin 309 days, NOACs 185 days  Bo et al., 201680 (2010–2013)  Effects of anticoagulation on AF patients aged ≥65 years, discharged from geriatric ward. Retrospective cohort study, Italy  n = 980  SPMSQ  Anticoagulation was associated with reduced mortality and better cognitive status: OR 2.29 (95% CI 1.47–3.57) adjusted for age, sex, congestive heart failure; HTN; aged≥75 years, diabetes, stroke, systemic embolism, vascular disease, abnormal renal/liver function, bleeding history, labile INR, drugs/alcohol.  age 83.4 ± 6.7 years, male 40%, follow-up 571 days  Bunch et al., 201681 (1994)  Prevalence of dementia in warfarin treated AF-patients and warfarin treated non-AF patients. Retrospective cohort study, United States  n = 10 537  ICD-9 + ICD-10  Warfarin treated AF patients with had a higher risk for dementia than warfarin treated non-AF patients HR = 2.42 (95% CI 1.85–3.18) adjusted analysis for age, sex, HTN, hyperlipidemia, diabetes, smoking, CHF, stroke, TIA, CAD, renal failure, prior CABG, PCI, bleed, malignancy, fall, and sleep apnea.  age 69.3 ± 10.9 years, male 52%, follow-up 2021 days  Moffitt et al., 201682 (studies from 1998–2015)  Meta-analysis of randomized controlled trials regarding cognition or dementia in patients with AF or atrial flutter.  n = 15876  MMSE  Potential benefit of anticoagulation in comparison to controls with antiplatelet therapy in patients with AF (or atrial flutter) over time, but no definitive evidence of cognitive benefit from anticoagulation treatment.  age/men n.a., follow-up 5.9 years  ICD, International Classification of Disease; MMSE, Mini Mental state Examination; CABG, coronary artery bypass graft surgery; PCI, percutaneous coronary intervention; HTN, hypertension; CHF, chronic heart failure; TIA, transient ischaemic attack; CAD, coronary artery disease; CVA, cerebrovascular accidents; MI, myocardial infarction; INR, international normalized ratio. Rhythm control therapy The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was the so far largest randomized trial comparing rate vs. rhythm control strategy. While the primary endpoint of AFFIRM was negative, a substudy including 245 AF patients did not show any difference regarding MMSE scores during a mean follow-up of 3.5 years.77 Best available evidence regarding left atrial catheter ablation is derived from the prospective Intermountain Atrial Fibrillation study,78 a case–control study based on a large healthcare database. Having included 16 848 patients with no history of AF, 4212 patients with symptomatic AF undergoing left atrial catheter ablation, and 16 848 non-ablated AF patients, this epidemiologic study is able to report associations but cannot establish causality. Over a period of 3 years, new onset AD was reported in 0.2% of AF patients who underwent left atrial catheter ablation compared to 0.9% of the non-ablated AF patients and 0.5% of the non-AF patients (p < 0.001). Other forms of incident dementia occurred in 0.4% of the AF ablation patients compared to 1.9% of the non-ablated AF patients and 0.7% of the non-AF patients (p < 0.001). Dementia was diagnosed by neurologists according to ICD-9. Unfortunately, anticoagulation rates and individualized medical therapy were not reported. At present, a large randomized trial is ongoing, investigating the potential benefit of early rhythm control in AF patients. The Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST) enrolled and randomized 2745 AF patients to rhythm control therapy based on antiarrhythmic drugs and catheter ablation or usual care following the 2010 European Society of Cardiology (ESC) guidelines. Cognitive function after 24 months of follow up is a secondary endpoint of EAST83 (Table 4) which will probably be reported in early 2019. Table 4 Ongoing AF studies focusing on cognition Study (Clintrials.gov)  Study design  Endpoint regarding cognition  EAST  Prospective, randomized, open, blinded outcome assessment trial. n = 2810  Secondary endpoint: MoCA 24 months after randomization.  NCT01288352  Early, comprehensive, rhythm control therapy in prevention of adverse cardiovascular outcomes in patients with AF compared to usual care.  BRAIN-AF  Prospective, randomized, double blind, efficacy study. n = 6396  Secondary endpoint: 3MS, MMSE and MoCA at any of the follow-up visits.  NCT02387229  Acetylsalicylic acid compared to rivaroxaban 15mg per day with regard to stroke prevention plus cognitive decline in non-valvular AF patients.  GIRAF  Prospective, randomized, open, blinded outcome assessment, efficacy study. n = 200  Primary outcome: cognitive impairment (MoCA + NINDS-CSN-Vascular Cognitive Impairment Harmonization) after 1 year and at the end of follow-up.  NCT01994265  Trial for the prevention of cognitive impairment in atrial fibrillation patients treated with dabigatran (150mg bid) or warfarin (targeting INR 2–3) for 2 years.  DIAL-F  Prospective case- control study. n = 888  Primary outcome: improvement or no-improvement in MoCA at baseline and at the 2-year follow-up.  NCT01816308  Incidence of cognitive impairments between AF patients undergoing either catheter ablation or remaining on anti-arrhythmic drugs at a 2-year follow-up.  SWISS-AF  Prospective observational, multicenter cohort study. n = 2600  Yearly clinical examination of neurocognitive function, MRI at baseline and 2 years follow-up.  NCT02105844  To increase knowledge on structural brain damage, the incidence and underlying mechanisms of cognitive decline in patients with atrial fibrillation.  Study (Clintrials.gov)  Study design  Endpoint regarding cognition  EAST  Prospective, randomized, open, blinded outcome assessment trial. n = 2810  Secondary endpoint: MoCA 24 months after randomization.  NCT01288352  Early, comprehensive, rhythm control therapy in prevention of adverse cardiovascular outcomes in patients with AF compared to usual care.  BRAIN-AF  Prospective, randomized, double blind, efficacy study. n = 6396  Secondary endpoint: 3MS, MMSE and MoCA at any of the follow-up visits.  NCT02387229  Acetylsalicylic acid compared to rivaroxaban 15mg per day with regard to stroke prevention plus cognitive decline in non-valvular AF patients.  GIRAF  Prospective, randomized, open, blinded outcome assessment, efficacy study. n = 200  Primary outcome: cognitive impairment (MoCA + NINDS-CSN-Vascular Cognitive Impairment Harmonization) after 1 year and at the end of follow-up.  NCT01994265  Trial for the prevention of cognitive impairment in atrial fibrillation patients treated with dabigatran (150mg bid) or warfarin (targeting INR 2–3) for 2 years.  DIAL-F  Prospective case- control study. n = 888  Primary outcome: improvement or no-improvement in MoCA at baseline and at the 2-year follow-up.  NCT01816308  Incidence of cognitive impairments between AF patients undergoing either catheter ablation or remaining on anti-arrhythmic drugs at a 2-year follow-up.  SWISS-AF  Prospective observational, multicenter cohort study. n = 2600  Yearly clinical examination of neurocognitive function, MRI at baseline and 2 years follow-up.  NCT02105844  To increase knowledge on structural brain damage, the incidence and underlying mechanisms of cognitive decline in patients with atrial fibrillation.  EAST, Early Treatment of Atrial Fibrillation for Stroke Prevention Trial; BRAIN-AF, Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation; GIRAF, Cognitive Impairment Related to Atrial Fibrillation Prevention Trial; DIAL-F, Cognitive Impairment in Atrial Fibrillation; SWISS-AF, Swiss Atrial Fibrillation Cohort Study; MoCA, Montreal Cognitive Assessment; 3MS, modified Mini-Mental-State; MMSE, Mini-Mental-State-Examination; NINDS-CSN, National Institute of Neurological Disorders and Stroke-Canadian Stroke Network. Anti-inflammatory drugs Since inflammatory pathways have been implicated as mechanisms leading to cognitive decline in AF patients, it is tempting to speculate whether anti-inflammatory drugs or statins may preserve cognitive function in these patients. However, it should be noted that until now no specific studies have been performed in AF patients to test this hypothesis. Therefore, we have to infer from studies in patients with high vascular risk. Statins have anti-inflammatory properties.84,85 In a substudy of the Cholesterol and Recurrent Events trial (CARE) randomizing 4150 patients 1:1 to placebo or 40 mg pravastatin per day, a significant increase in CRP levels in the placebo group was detected after a follow-up of 5 years.86 A retrospective National Health Insurance Research Database analysis, including more than 51 000 Taiwanese AF patients and 200 000 controls without dementia, recently demonstrated an association of statin treatment with a reduced risk for non-vascular dementia [HR 0.83 (95% CI 0.80–0.86)] during a follow-up of 10 years.87 This protective effect of statins was obviously not AF-specific, because pooled analyses from eight non-randomized studies88–96 including more than 23 400 non-AF statin-treated patients reported a HR of 0.71 (95% CI 0.61–0.82) for dementia during a follow-up of 3 to 24 years.97 In contrast, however, an ‘antidementive’ effect of statins was not observed in the HPS and the PROSPER trial, evaluating non-AF patients aged 70 years or older randomized to either 40 mg of simvastatin (HPS) or 40 mg pravastatin (PROSPER) per day or placebo during a follow up of 5 years.98 Another potential treatment target might be TNF-α mediated neurotoxicity. Perispinal application of etanercept in more than 600 stroke-patients resulted in a significant improvement of cognition and psychological/behavioral function according to a retrospective chart-analysis.99 However, the study has several methodological weaknesses, and the results have to be confirmed in a controlled setting. Large ongoing AF trials focusing on cognition The advent of non-vitamin K dependent oral anticoagulants (NOACs) and their increasing use in clinical practice will probably help to shed more light on the impact of oral anticoagulation on cognitive function in AF patients. While comparing rivaroxaban to acetylsalicylic acid in AF patients with low risk of stroke, the prospective, randomized, double-blind Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF) study has a secondary endpoint on cognition. Moreover, the primary endpoint of the Cognitive Impairment Related to Atrial Fibrillation Prevention (GIRAF) study comparing dabigatran to warfarin is cognitive function over a period of 2 years. Besides the aforementioned EAST study,83 the primary endpoint of the case-control study Cognitive Impairment in Atrial Fibrillation (DIAL-F)—comparing catheter ablation to anti-arrhythmic drug treatment—is focusing on rhythm control and cognitive decline. Moreover, the large observational SWISS-AF study includes neuropsychological testing in AF patients undergoing repeated brain imaging (Table 4). Implications for the future Long-term longitudinal studies are needed to unequivocally address the impact of AF on cognition (as opposed to other concomitant co-morbidities and risk factors). In more detail, humoral or blood-flow dependent mechanisms by which AF may contribute to cognitive decline should be deciphered. In addition, large AF treatment trials should focus on cognition and dementia as an independent endpoint. Future trials should further clarify whether serial assessment of cardiac function and cardiac rhythm may be beneficial in subjects presenting with cognitive impairment. Whether isolated atrial amyloidosis not only increases the risk of AF100 but is also linked to the amyloid deposits observed in Alzheimeŕs dementia needs further investigation. Conclusions AF and dementia are both frequent diseases with substantial socioeconomic impact on the ageing society. Despite of overlapping cardiovascular risk factors, growing evidence from prospective studies supports the hypothesis that AF is an independent risk factor for cognitive decline and dementia, also including AD. Potential pathomechanisms of AF-related dementia are obviously AF-related (clinically overt or silent) strokes and systemic inflammation. Whether chronic hypoperfusion of the brain is relevant for the development of Alzheimer’s remains unclear, in particular when considering the preventive effect of antihypertensive drugs. Well-designed randomized trials, accompanied by a standardised cognitive assessment, are urgently needed to identify (novel) treatment options to prevent cognitive decline in AF patients. Acknowledgements We thank Julia Herde for reviewing the manuscript and Bob Siegerink for supporting the chapter on epidemiology (Center for Stroke Research Berlin, Germany). Conflict of interest: Joanna Dietzel reports no conflict of interests. Karl Georg Haeusler reports speaker's honoraria, consulting fees, lecture honoraria, and study grants from Bayer Healthcare, Boehringer Ingelheim, Sanofi, Medtronic, Pfizer, and Bristol-Myers Squibb. Matthias Endres reports lecture fees and study grants by Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Ever, Glaxo Smith Kline, MSD, Novartis, and Pfizer. Funding K.G.H. received funding from the BMBF (Center for Stroke Research Berlin) and DZHK. M.E. has received funding from the DFG (NeuroCure, SFB TR 43, KFO 247), BMBF (Center for Stroke Research Berlin), DZHK, EU (European Stroke Network, WakeUp, Counterstroke), Corona Foundation (Vascular Senescence); Fondation Leducq. References 1 Cohen MB, Mather PJ. A review of the association between congestive heart failure and cognitive impairment. Am J Geriatr Cardiol  2007; 16: 171– 4. Google Scholar CrossRef Search ADS PubMed  2 Thacker EL, Gillett SR, Wadley VG, Unverzagt FW, Judd SE, McClure LA et al.   The American Heart Association Life's Simple 7 and incident cognitive impairment: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study. J Am Heart Assoc  2014;11; 3: e000635. Google Scholar CrossRef Search ADS PubMed  3 Wu YT, Fratiglioni L, Matthews FE, Lobo A, Breteler MM, Skoog I et al.   Dementia in western Europe: epidemiological evidence and implications for policy making. Lancet Neurol  2016; 15: 116– 24. Google Scholar CrossRef Search ADS PubMed  4 Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement  2013; 9: 63– 75.e2. Google Scholar CrossRef Search ADS PubMed  5 Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol  2014; 16: 213– 20. Google Scholar CrossRef Search ADS   6 Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH et al.   Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J  2006; 27: 949– 53. Google Scholar CrossRef Search ADS PubMed  7 Connolly A, Gaehl E, Martin H, Morris J, Purandare N. Underdiagnosis of dementia in primary care: variations in the observed prevalence and comparisons to the expected prevalence. Aging Ment Health  2011; 15: 978– 84. Google Scholar CrossRef Search ADS PubMed  8 Erkinjuntti T, Ostbye T, Steenhuis R, Hachinski V. The effect of different diagnostic criteria on the prevalence of dementia. N Engl J Med  1997; 337: 1667– 74. Google Scholar CrossRef Search ADS PubMed  9 Wancata J, Börjesson-Hanson A, Ostling S, Sjögren K, Skoog I. Diagnostic criteria influence dementia prevalence. Am J Geriatr Psychiatry  2007; 15: 1034– 45. Google Scholar CrossRef Search ADS PubMed  10 Chen Y, Szoeke C, Woodward M. Performance of the different proposed criteria for the diagnosis of mild cognitive impairment and Alzheimer's disease: data from the Australian imaging, biomarkers and lifestyle study of aging. Alzheimers Dement  2013; 9: P755– 6. Google Scholar CrossRef Search ADS   11 Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B et al.   2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace  2016; 8: 1609– 78. Google Scholar CrossRef Search ADS   12 Svennberg E, Engdahl J, Al-Khalili F, Friberg L, Frykman V, Rosenqvist M. Mass screening for untreated atrial fibrillation: the STROKESTOP study. Circulation  2015; 131: 2176– 84. Google Scholar CrossRef Search ADS PubMed  13 Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S et al.   Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). European Heart Rhythm Association1; European Association for Cardio-Thoracic Surgery; ESC Committee for Practice Guidelines. Europace  2010; 12: 1360– 420. Google Scholar CrossRef Search ADS PubMed  14 Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA et al.   ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace  2006; 8: 651– 745. Google Scholar CrossRef Search ADS PubMed  15 Glotzer TV, Ziegler PD. Cryptogenic stroke: is silent atrial fibrillation the culprit? Heart Rhythm  2015; 12: 234– 41. Google Scholar CrossRef Search ADS PubMed  16 Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA et al.   CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med  2014; 370: 2478– 86. Google Scholar CrossRef Search ADS PubMed  17 Lowres N, Neubeck L, Redfern J, Freedman SB. Screening to identify unknown atrial fibrillation. A systematic review. Thromb Haemost  2013; 110: 213– 22. Google Scholar CrossRef Search ADS PubMed  18 Dussault C, Toeg H, Nathan M, Wang ZJ, Roux JF, Secemsky E. Electrocardiographic monitoring for detecting atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol  2015; 8: 263– 9. Google Scholar CrossRef Search ADS PubMed  19 Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol  2004; 61: 661– 6. Google Scholar CrossRef Search ADS PubMed  20 Iguchi Y, Kimura K, Aoki J, Kobayashi K, Terasawa Y, Sakai K et al.   Prevalence of atrial fibrillation in community-dwelling Japanese aged 40 years or older in Japan: analysis of 41,436 non-employee residents in Kurashiki-city. Circ J  2008; 72: 909– 13. Google Scholar CrossRef Search ADS PubMed  21 Hailpern SM, Melamed ML, Cohen HW, Hostetter TH. Moderate chronic kidney disease and cognitive function in adults 20 to 59 years of age: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol  2007; 18: 2205– 13. Google Scholar CrossRef Search ADS PubMed  22 Liao JN, Chao TF, Liu CJ, Wang KL, Chen SJ, Lin YJ et al.   Incidence and risk factors for new-onset atrial fibrillation among patients with end-stage renal disease undergoing renal replacement therapy. Kidney Int  2015; 87: 1209– 15. Google Scholar CrossRef Search ADS PubMed  23 Spira AP, Blackwell T, Stone KL, Redline S, Cauley JA, Ancoli-Israel S et al.   Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc  2008; 56: 45– 50. Google Scholar CrossRef Search ADS PubMed  24 Gami AS, Hodge DO, Herges RM, Olson EJ, Nykodym J, Kara T et al.   Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol  2007; 49: 565– 71. Google Scholar CrossRef Search ADS PubMed  25 Böhm M, Schumacher H, Leong D, Mancia G, Unger T, Schmieder R et al.   Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk. Hypertension  2015; 65: 651– 61. Google Scholar CrossRef Search ADS PubMed  26 Tremblay-Gravel M, White M, Roy D, Leduc H, Wyse DG, Cadrin-Tourigny J et al.   Blood pressure and atrial fibrillation: a combined AF-CHF and AFFIRM analysis. J Cardiovasc Electrophysiol  2015; 26: 509– 14. Google Scholar CrossRef Search ADS PubMed  27 Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L. Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med  2006; 166: 1003– 8. Google Scholar CrossRef Search ADS PubMed  28 Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA  1994; 271: 840– 4. Google Scholar CrossRef Search ADS PubMed  29 Roberts RO, Knopman DS, Geda YE, Cha RH, Roger VL, Petersen RC. Coronary heart disease is associated with non-amnestic mild cognitive impairment. Neurobiol Aging  2010; 31: 1894– 902. Google Scholar CrossRef Search ADS PubMed  30 Mukamal KJ, Kuller LH, Fitzpatrick AL, Longstreth WTJr, Mittleman MA, Siscovick DS. Prospective study of alcohol consumption and risk of dementia in older adults. JAMA  2003; 289: 1405– 13. Google Scholar CrossRef Search ADS PubMed  31 Mukamal KJ, Tolstrup JS, Friberg J, Jensen G, Grønbaek M. Alcohol consumption and risk of atrial fibrillation in men and women: the Copenhagen City Heart Study. Circulation  2005; 112: 1736– 42. Google Scholar CrossRef Search ADS PubMed  32 Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study. The Rotterdam Study. Stroke  1997; 28: 316– 21. Google Scholar CrossRef Search ADS PubMed  33 Elias MF, Sullivan LM, Elias PK, Vasan RS, D'Agostino RBSr, Seshadri S et al.   Atrial fibrillation is associated with lower cognitive performance in the Framingham offspring men. J Stroke Cerebrovasc Dis  2006; 15: 214– 22. Google Scholar CrossRef Search ADS PubMed  34 Knecht S, Oelschläger C, Duning T, Lohmann H, Albers J, Stehling C et al.   Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J  2008; 29: 2125– 32. Google Scholar CrossRef Search ADS PubMed  35 Bunch TJ, Weiss JP, Crandall BG, May HT, Bair TL, Osborn JS et al.   Atrial fibrillation is independently associated with senile, vascular, and Alzheimer's dementia. Heart Rhythm  2010; 7: 433– 7. Google Scholar CrossRef Search ADS PubMed  36 Marzona I, O'Donnell M, Teo K, Gao P, Anderson C, Bosch J et al.   Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ  2012; 184: E329– 36. Google Scholar CrossRef Search ADS PubMed  37 Thacker EL, McKnight B, Psaty BM, Longstreth WTJr, Sitlani CM, Dublin S et al.   Atrial fibrillation and cognitive decline: a longitudinal cohort study. Neurology  2013; 81: 119– 25. Google Scholar CrossRef Search ADS PubMed  38 de Bruijn RF, Heeringa J, Wolters FJ, Franco OH, Stricker BH, Hofman A et al.   Association between atrial fibrillation and dementia in the general population. JAMA Neurol  2015; 72: 1288– 94. Google Scholar CrossRef Search ADS PubMed  39 Santangeli P, Di Biase L, Bai R, Mohanty S, Pump A, Cereceda Brantes M et al.   Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm  2012; 9: 1761– 8. Google Scholar CrossRef Search ADS PubMed  40 Tilvis RS, Kähönen-Väre MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE. Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci  2004; 59: 268– 74. Google Scholar CrossRef Search ADS PubMed  41 Forti P, Maioli F, Pisacane N, Rietti E, Montesi F, Ravaglia G. Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment (MCI). Arch Gerontol Geriatr  2007; 44(Suppl 1): 155– 65. Google Scholar CrossRef Search ADS PubMed  42 Marengoni A, Qiu C, Winblad B, Fratiglioni L. Atrial fibrillation, stroke and dementia in the very old: a population-based study. Neurobiol Aging  2011; 32: 1336– 7. Google Scholar CrossRef Search ADS PubMed  43 Peters R, Poulter R, Beckett N, Forette F, Fagard R, Potter J et al.   Cardiovascular and biochemical risk factors for incident dementia in the Hypertension in the Very Elderly Trial. J Hypertens  2009; 27: 2055– 62. Google Scholar CrossRef Search ADS PubMed  44 Dublin S, Anderson ML, Haneuse SJ, Heckbert SR, Crane PK, Breitner JC et al.   Atrial fibrillation and risk of dementia: a prospective cohort study. J Am Geriatr Soc  2011; 59: 1369– 75. Google Scholar CrossRef Search ADS PubMed  45 Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med  2013; 158: 338– 46. Google Scholar CrossRef Search ADS PubMed  46 Leys D, Hénon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol  2005; 4: 752– 9. Google Scholar CrossRef Search ADS PubMed  47 Poggesi A, Inzitari D, Pantoni L. Atrial fibrillation and cognition: epidemiological data and possible mechanisms. Stroke  2015; 46: 3316– 21. Google Scholar CrossRef Search ADS PubMed  48 Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ  2010;26; 341: c3666. Google Scholar CrossRef Search ADS PubMed  49 Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol  2015; 11: 157– 65. Google Scholar CrossRef Search ADS PubMed  50 Haeusler KG, Wilson D, Fiebach JB, Kirchhof P, Werring DJ. Brain MRI to personalise atrial fibrillation therapy: current evidence and perspectives. Heart  2014; 100: 1408– 13. Google Scholar CrossRef Search ADS PubMed  51 Haeusler KG, Laufs U, Endres M. Chronic heart failure and ischemic stroke. Stroke  2011; 42: 2977– 82. Google Scholar CrossRef Search ADS PubMed  52 Zuccalà G, Cattel C, Manes-Gravina E, Di Niro MG, Cocchi A, Bernabei R. Left ventricular dysfunction: a clue to cognitive impairment in older patients with heart failure. J Neurol Neurosurg Psychiatry  1997; 63: 509– 12. Google Scholar CrossRef Search ADS PubMed  53 Jefferson AL, Himali JJ, Au R, Seshadri S, Decarli C, O'Donnell CJ et al.   Relation of left ventricular ejection fraction to cognitive aging (from the Framingham Heart Study). Am J Cardiol  2011; 108: 1346– 51. Google Scholar CrossRef Search ADS PubMed  54 de Bruijn RF, Portegies ML, Leening MJ, Bos MJ, Hofman A, van der Lugt A et al.   Subclinical cardiac dysfunction increases the risk of stroke and dementia: the Rotterdam Study. Neurology  2015; 84: 833– 40. Google Scholar CrossRef Search ADS PubMed  55 Alosco ML, Spitznagel MB, Sweet LH, Josephson R, Hughes J, Gunstad J. Atrial fibrillation exacerbates cognitive dysfunction and cerebral perfusion in heart failure. Pacing Clin Electrophysiol  2015; 38: 178– 86. Google Scholar CrossRef Search ADS PubMed  56 de la Torre JC. Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesis. Neurobiol Aging  2000; 21: 331– 42. Google Scholar CrossRef Search ADS PubMed  57 de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke  2002; 33: 1152– 62. Google Scholar CrossRef Search ADS PubMed  58 Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res  1990; 66: 8– 17. Google Scholar CrossRef Search ADS PubMed  59 Stulak JM, Dearani JA, Daly RC, Zehr KJ, Sundt TMIII, Schaff HV. Left ventricular dysfunction in atrial fibrillation: restoration of sinus rhythm by the Cox-maze procedure significantly improves systolic function and functional status. Ann Thorac Surg  2006; 82: 494– 500. Google Scholar CrossRef Search ADS PubMed  60 Nabauer M, Gerth A, Limbourg T, Schneider S, Oeff M, Kirchhof P et al.   The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace  2009; 11: 423– 34. Google Scholar CrossRef Search ADS PubMed  61 Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol  2012; 60: 2263– 70. Google Scholar CrossRef Search ADS PubMed  62 Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol  2007; 50: 2021– 8. Google Scholar CrossRef Search ADS PubMed  63 Rotter M, Jaïs P, Vergnes MC, Nurden P, Takahashi Y, Sanders P et al.   Decline in C-reactive protein after successful ablation of long-lasting persistent atrial fibrillation. J Am Coll Cardiol  2006; 47: 1231– 3. Google Scholar CrossRef Search ADS PubMed  64 Marcus GM, Smith LM, Ordovas K, Scheinman MM, Kim AM, Badhwar N et al.   Intracardiac and extracardiac markers of inflammation during atrial fibrillation. Heart Rhythm  2010; 7: 149– 154. Google Scholar CrossRef Search ADS PubMed  65 Ohara K, Inoue H, Nozawa T, Hirai T, Iwasa A, Okumura K et al.   Accumulation of risk factors enhances the prothrombotic state in atrial fibrillation. Int J Cardiol  2008; 126: 316– 21. Google Scholar CrossRef Search ADS PubMed  66 Kallergis EM, Manios EG, Kanoupakis EM, Mavrakis HE, Kolyvaki SG, Lyrarakis GM et al.   The role of the post-cardioversion time course of hs-CRP levels in clarifying the relationship between inflammation and persistence of atrial fibrillation. Heart  2008; 94: 200– 4. Google Scholar CrossRef Search ADS PubMed  67 Bou Khalil R, Khoury E, Koussa S. Linking multiple pathogenic pathways in Alzheimer's disease. World J Psychiatry  2016;22; 6: 208– 14. Google Scholar CrossRef Search ADS PubMed  68 Wersching H, Duning T, Lohmann H, Mohammadi S, Stehling C, Fobker M et al.   Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology  2010; 74: 1022– 9. Google Scholar CrossRef Search ADS PubMed  69 Pinto A, Tuttolomondo A, Casuccio A, Di Raimondo D, Di Sciacca R, Arnao V et al.   Immuno-inflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF). Clin Sci (Lond)  2009; 116: 781– 9. Google Scholar CrossRef Search ADS PubMed  70 Bolz SS, Vogel L, Sollinger D, Derwand R, Boer C, Pitson SM et al.   Sphingosine kinase modulates microvascular tone and myogenic responses through activation of RhoA/Rho kinase. Circulation  2003; 108: 342– 7. Google Scholar CrossRef Search ADS PubMed  71 Yang J, Noyan-Ashraf MH, Meissner A, Voigtlaender-Bolz J, Kroetsch JT, Foltz W et al.   Proximal cerebral arteries develop myogenic responsiveness in heart failure via tumor necrosis factor-α-dependent activation of sphingosine-1-phosphate signaling. Circulation  2012; 126: 196– 206. Google Scholar CrossRef Search ADS PubMed  72 Sairanen T, Carpén O, Karjalainen-Lindsberg ML, Paetau A, Turpeinen U, Kaste M et al.   Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke  2001; 32: 1750– 8. Google Scholar CrossRef Search ADS PubMed  73 Pan JP, Liu TY, Chiang SC, Lin YK, Chou CY, Chan WL et al.   The value of plasma levels of tumor necrosis factor-alpha and interleukin-6 in predicting the severity and prognosis in patients with congestive heart failure. J Chin Med Assoc  2004; 67: 222– 8. Google Scholar PubMed  74 Yagi K, Lidington D, Wan H, Fares JC, Meissner A, Sumiyoshi M et al.   Therapeutically targeting tumor necrosis factor-α/sphingosine-1-phosphate signaling corrects myogenic reactivity in subarachnoid hemorrhage. Stroke  2015; 46: 2260– 70. Google Scholar CrossRef Search ADS PubMed  75 Jacobs V, Woller SC, Stevens S, May HT, Bair TL, Anderson JL et al.   Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm  2014; 11: 2206– 13. Google Scholar CrossRef Search ADS PubMed  76 Bunch TJ, May HT, Bair TL, Crandall BG, Cutler MJ, Day JD et al.   Atrial fibrillation patients treated with long-term warfarin anticoagulation have higher rates of all dementia types compared with patients receiving long-term warfarin for other indications. J Am Heart Assoc  2016; 5. e003932. Google Scholar CrossRef Search ADS PubMed  77 Chung MK, Shemanski L, Sherman DG, Greene HL, Hogan DB, Kellen JC et al.   AFFIRM Investigators. Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy. J Am Coll Cardiol  2005; 46: 1891– 9. Google Scholar CrossRef Search ADS PubMed  78 Bunch TJ, Crandall BG, Weiss JP, May HT, Bair TL, Osborn JS et al.   Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. Cardiovasc Electrophysiol  2011; 22: 839– 45. Google Scholar CrossRef Search ADS   79 Mavaddat N, Roalfe A, Fletcher K, Lip GY, Hobbs FD, Fitzmaurice D et al.   Warfarin versus aspirin for prevention of cognitive decline in atrial fibrillation: randomized controlled trial (Birmingham Atrial Fibrillation Treatment of the Aged Study). Stroke  2014; 45: 1381– 6. Google Scholar CrossRef Search ADS PubMed  80 Jacobs V, May HT, Bair TL, Crandall BG, Cutler MJ, Day JD et al.   Long-term population-based cerebral ischemic event and cognitive outcomes of direct oral anticoagulants compared with warfarin among long-term anticoagulated patients for atrial fibrillation. Am J Cardiol  2016; 118: 210– 4. Google Scholar CrossRef Search ADS PubMed  81 Bo M, Sciarrillo I, Li Puma F, Badinella Martini M, Falcone Y, Iacovino M et al.   Effects of oral anticoagulant therapy in medical inpatients ≥65 years with atrial fibrillation. Am J Cardiol  2016; 117: 590– 5. Google Scholar CrossRef Search ADS PubMed  82 Moffitt P, Lane DA, Park H, O'Connell J, Quinn TJ. Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review. Age Ageing  2016; 45: 767– 75. Google Scholar CrossRef Search ADS PubMed  83 Kirchhof P, Breithardt G, Camm AJ, Crijns HJ, Kuck KH, Vardas P et al.   Improving outcomes in patients with atrial fibrillation: rationale and design of the Early treatment of Atrial fibrillation for Stroke prevention Trial. Am Heart J  2013; 166: 442– 8. Google Scholar CrossRef Search ADS PubMed  84 Keidar S, Aviram M, Maor I, Oiknine J, Brook JG. Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein receptor activity in macrophages: in vitro and in vivo studies. Br J Clin Pharmacol  1994; 38: 513– 9. Google Scholar CrossRef Search ADS PubMed  85 Aikawa M, Rabkin E, Okada Y, Voglic SJ, Clinton SK, Brinckerhoff CE et al.   Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation  1998; 97: 2433– 44. Google Scholar CrossRef Search ADS PubMed  86 Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation  1999; 100: 230– 5. Google Scholar CrossRef Search ADS PubMed  87 Chao TF, Liu CJ, Chen SJ, Wang KL, Lin YJ, Chang SL et al.   Statins and the risk of dementia in patients with atrial fibrillation: a nationwide population-based cohort study. Int J Cardiol  2015; 196: 91– 7. Google Scholar CrossRef Search ADS PubMed  88 Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M et al.   Cache County Study investigators. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry  2005; 62: 217– 24. Google Scholar CrossRef Search ADS PubMed  89 Bettermann K, Arnold AM, Williamson J, Rapp S, Sink K, Toole JF et al.   Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study. J Stroke Cerebrovasc Dis  2012; 21: 436– 44. Google Scholar CrossRef Search ADS PubMed  90 Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry  2009; 80: 13– 7. Google Scholar CrossRef Search ADS PubMed  91 Rea TD, Breitner JC, Psaty BM, Fitzpatrick AL, Lopez OL, Newman AB et al.   Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol  2005; 62: 1047– 51. Google Scholar CrossRef Search ADS PubMed  92 Beydoun MA, Beason-Held LL, Kitner-Triolo MH, Beydoun HA, Ferrucci L, Resnick SM et al.   Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment. J Epidemiol Community Health  2011; 65: 949– 57. Google Scholar CrossRef Search ADS PubMed  93 Li G, Shofer JB, Rhew IC, Kukull WA, Peskind ER, McCormick W et al.   Age-varying association between statin use and incident Alzheimer's disease. J Am Geriatr Soc  2010; 58: 1311– 7. Google Scholar CrossRef Search ADS PubMed  94 Arvanitakis Z, Schneider JA, Wilson RS, Bienias JL, Kelly JF, Evans DA et al.   Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology  2008; 70: 1795– 802. Google Scholar CrossRef Search ADS PubMed  95 Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology  2008; 71: 344– 50. Google Scholar CrossRef Search ADS PubMed  96 Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med  2007;19; 5: 20. Google Scholar CrossRef Search ADS PubMed  97 Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc  2013; 88: 1213– 21. Google Scholar CrossRef Search ADS PubMed  98 McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev  2009; CD003160. 99 Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, DePuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs  2012; 26: 1051– 70. Google Scholar CrossRef Search ADS PubMed  100 Röcken C, Peters B, Juenemann G, Saeger W, Klein HU, Huth C et al.   Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation  2002; 106: 2091– 7. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Journal

EuropaceOxford University Press

Published: Mar 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve Freelancer

DeepDyve Pro

Price
FREE
$49/month

$360/year
Save searches from
Google Scholar,
PubMed
Create lists to
organize your research
Export lists, citations
Read DeepDyve articles
Abstract access only
Unlimited access to over
18 million full-text articles
Print
20 pages/month
PDF Discount
20% off