Background: The NIA-AA research framework proposes a biological definition of Alzheimer’sdisease, where asymptomatic persons with amyloid deposition would be considered as having this disease prior to symptoms. Discussion: Notwithstanding the fact that amyloid deposition in isolation is not associated with dementia, even the combined association of amyloid and tau pathology does not inevitably need to dementia over age 65. Other pathological factors may play a leading or an accelerating role in age-associated cognitive decline, including vascular small vessel disease, neuroinflammation and Lewy Body pathology. Conclusion: Research should aim at understanding the interaction between all these factors, rather than focusing on them individually. Hopefully this will lead to a personalized approach to the prevention of brain aging, based on individual biological, genetic and cognitive profiles. Keywords: Alzheimer’s disease, Diagnosis, Treatment, Biomarkers, Precision medicine, Translational research, Brain imaging, Database analysis, Human volunteer cohorts Background these interventions along the continuum of AD neuro- The treatment of Alzheimer’s disease (AD) is currently degeneration over time. symptomatic and based on neurotransmitter manipula- This review wants to highlight the facts that other tion, akin to what has been achieved in Parkinson’s pathological factors are at play in AD, and deserve con- disease. Thus acetycholine activity is being increased by sideration in the full diagnostic assessment of the pa- cholinesterase inhibitors, and glutamatergic activity is tients, and for treatment. These factors are vascular being dampened by memantine action on NMDA recep- changes, Lewy body pathology and neuroinflammation. tors. A modest but clinically detectable response is present in many patients using such drugs alone or in combination. Classic pathology of AD Unfortunately the next generation of drugs acting on The clinical progression of AD is linked to specific neuro- AD core pathological factors such as amyloid deposition pathological features, such as extracellular deposition of and phosphorylated tau aggregation has failed so far to Aβ plaques, intracellular inclusions of tau protein in delay disease progression, raising the issue of timing of neurofibrillary tangles, and neuronal degeneration. The discovery and advance of disease biomarkers over the last decade have significantly advanced our understanding of * Correspondence: email@example.com the dynamic pathophysiological changes underlying AD McGill Center for Studies in Aging, Douglas Mental Health Research and have allowed the detection of AD pathophysiology in Institute, Montreal, Canada Full list of author information is available at the end of the article vivo . Given that the presence of AD pathophysiology © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gauthier et al. Translational Neurodegeneration (2018) 7:12 Page 2 of 7 has been found across a broad clinical spectrum including for both ischemic and hemorrhagic CVD . There is individuals asymptomatic and with mild cognitive symp- increasingly robust relationship between other risk fac- toms, biomarkers now play an important role in charac- tors including hypertension, diabetes, atrial fibrillation, terizing the trajectory of AD pathophysiology and have hypercholesterolemia, smoking, hyperhomocysteinaemia, been incorporated in the AD diagnostic research criteria age and obesity and AD, whereas there are possible [2–5]. These diagnostic research criterions recognize that protective effect of the ‘Mediterranean’ diet and physical the coexistence of abnormal Aβ and tau biomarkers better exercise [9–14]. Although not all studies have found a identify the preclinical and MCI individuals who will pro- correlation between vascular risk factors and AA [15, gress to dementia over relatively short time frames of 16], it has been reported that the presence of vascular three to 5 years. risk factors can predict the development of AD or the Based on histopathological and genetic evidences, fi- conversion from mild cognitive impairment (MCI) to brillar Aβ, the main constituent of Aβ plaques, has been AD [9, 17, 18]. postulated as the major driving force leading to AD de- Most AD patients have structural changes in their cere- mentia (Aβ cascade hypothesis). According to this hy- bral blood vessels. Imaging and pathological studies have pothesis, all the resulting pathological processes are due demonstrated a high prevalence of arteriolosclerotic small to an imbalance between Aβ production and clearance, vessel disease (SVD) in AD patients. Post-mortem and im- which would then potentiate the spread of tauopathy, aging studies demonstrate that arteriolar Aβ amyloid leading to neurodegeneration and cognitive decline. angiopathy, a sub-type of SVD, is more common in pa- However, the lack of consistent association between Aβ tients with AD than in elderly controls [19–23]. The amyl- and clinical progression, and the fact that amyloid path- oid angiopathy mainly affects the leptomeningeal, cortical ology has been found in cognitively normal elderly indi- and capillary vessel walls, but sometimes the cerebellum, viduals challenge the Aβ hypothesis in its original form. and occasionally the brainstem [12, 24]. In the autopsy studies, it suggests that AD is correlated with atheroscler- Proposal for a new classification system osis of the Circle of Willis, and the severity of the athero- An unbiased biomarker classification system, A/T/N, sclerosis is associated with neuritic plaques and which avoids the assumptions of the temporal ordering neurofibrillary tangles [25–27]. of AD biomarkers, has been proposed . In this classi- An important component of CVD in AD is cerebral fication system where each biomarker category is binar- hypoperfusion, which can be present several years before ized as either positive or negative, “A” represents Aβ the onset of clinical symptoms. The diffusion pattern of biomarkers using amyloid PET or CSF Aβ , “T” repre- cerebral hypoperfusion is stereotyped in AD: the first af- sents tau biomarkers using CSF p-tau or tau PET, and fected area of is the precuneus, which has appeared “N” represents neurodegeneration biomarkers using CSF 10 years before the onset of AD, followed by the cingu- p-tau, structural MRI or [ F]fluorodeoxyglucose PET late gyrus and the lateral part of the parietal lobe, then (FDG). This descriptive classification aims to organize the frontal and temporal lobes, and the eventually the the multi-modality biomarker results at the individual cerebrum . The main mechanism of cerebral hypo- person level in a way that is easy to adopt and interpret. perfusion in AD may be non-structural . In vivo and Other brain pathological processes have been postulated in vitro studies have shown cerebral hypoperfusion in- as natural candidates to integrate this unbiased system. creases the production of Aβ and tau hyperphosphoryla- Studies under way are measuring simultaneously the tion, reduces the clearance of Aβ, then aggravates the amyloid, tau, and neuroinflammation in individuals, with progress of AD [28–33]. There is good evidence that Aβ follow-up over time to test the hypothesis that the coex- amyloid angiopathy and SVD are associated with infarc- istence of the brain pathological factors may accelerates tion and cerebral hemorrhage in AD [34–43]. The AD clinical manifestations. mechanisms may involve susceptibility to thrombosis, We argue that the A/T/N classification may be broad- reduction of blood flow, impaired caliber regulation, and ened to include other key pathological factors: vascular impaired function of the blood-brain barrier (BBB). In- pathology, Lewy Body pathology and neuroinflammation. farction or bleeding will reduce the threshold for the on- set of AD, and is considered as an important risk factor Vascular changes for the clinical manifestations of AD [44, 45]. There is growing evidence that AD often coexists with The links between vascular factors and AD have been cerebrovascular disease (CVD). They share many risk clearly confirmed both clinically and pathologically. How- factors, leading to additive or synergistic effects on cog- ever, there is a lack of high-quality therapeutic research to nitive decline . The APOE ε4 allele is the strongest examine the extent to which vascular risk changes alter genetic risk factor for late-onset AD, and APOE ε4is the course of AD. Further longitudinal mechanisms and also associated with increasing burden in MRI markers therapeutic studies are needed, especially to determine Gauthier et al. Translational Neurodegeneration (2018) 7:12 Page 3 of 7 whether the treatment of vascular risk factors can prevent APOE ε4 carriers than AD individuals without Lewy or delay the onset of AD. bodies. Moreover, this study also suggested that halluci- nations, motor disturbs, and sleep problems are more Lewy body pathology severe in AD individuals with Lewy bodies than in the Although the accumulation of amyloid protein in plaques ones without Lewy bodies . and tau protein in neurofibrillary tangles constitutes the The α-synuclein protein, which in the main constitu- core pathological feature of AD, the presence of abnormal ent of the Lewy bodies, can be measured in the cerebro- brain aggregates of a third proteinopathy has been shown spinal fluid (CSF) of living people . Some CSF to be very prevalent in moderate and severe AD [46–48]. studies have reported an increase in α-synuclein levels in Cytoplasmic inclusions of α-synuclein intraneuronally in patients with MCI and AD as compared to controls Lewy bodies have been reported in up to 50% of sporadic [72–74], whereas other studies have shown no difference AD cases and up to 60% of familial AD cases [49–52]. In or reduced levels across the AD clinical spectrum [75– the context of AD, it is still unclear whether the overlap 77]. The levels of α-synuclein have shown positive cor- between Lewy bodies and the hallmark AD proteins relation with CSF tau pathology in some studies [73, 77] occurs due to a mere co-occurrence of independent and no correlation in another . pathological processes or is the manifestation of intercon- Although the characteristic topographic presentation nected pathological processes. and the frequency of Lewy bodies in AD suggest a po- Histopathological studies have shown that Lewy bodies tential common mechanism for AD and Lewy bodies, normally accumulate in a specific topographic brain pat- the divergence in results between studies indicates that tern, starting in the brainstem and subsequently extend- further studies are imperative to clarify the role of Lewy ing to the limbic and neocortical brain regions . In body pathology in AD. One of the main limitations of contrast, in AD patients the Lewy bodies deposition con- the current studies is the absence of an imaging agent centrates in the amygdala with little deposition in the able to capture Lewy bodies in the living brain. Many brainstem or neocortex . This characteristic pattern groups are trying in developing such an imaging agent of deposition has been called AD with amygdala Lewy in order to provide the means to definitively clarify the bodies [47, 54]. Interestingly, the Lewy bodies in the dynamical changes of Lewy bodies in the human brain amygdala normally overlap with tau accumulation  and its interplay with amyloid, tau, neuroinflammation, and neuronal loss , suggesting that pathological and vascular pathology. interaction between these pathologies may play a role in the progression of AD. The severity of the pathology in Neuroinflammation the amygdala correlates with disease duration [55, 56] In addition to hallmark AD neuropathological features and emotional and memory difficulties , which sug- such as amyloid (Aβ) plaques, neurofibrillary tangles and gest that the aforementioned interaction plays a role in neuronal degeneration, there is a growing body of evi- the AD clinical phenotype in this group of individuals dence supporting neuroinflammation as an important . Moreover, the cortical concentrations of Lewy bod- player in the pathogenesis of AD [79, 80]. Neuropatho- ies have been correlated with amyloid burden [59, 60] logical studies have shown the presence of activated and neurofibrillary tangles [61, 62]. microglia and inflammation related mediators in AD Postmortem observations focusing on the influence of brains of low Braak stage , while genetic studies Lewy bodies and the phonotypical presentation of AD show that several genes that increase the risk of sporadic have shown inconsistent results. These studies presented AD encode factors that regulate microglial clearance of opposing results whether the presence of Lewy bodies in misfolded proteins and inflammatory reaction, such as AD patients has an effect on the age of onset of symp- TREM2 and CD33 [82, 83]. Epidemiological studies fur- toms, death [51, 63–65], the likelihood of be an APOE ther suggest that non-steroidal anti-inflammatory drugs ε4 carrier [51, 65, 66], parkinsonian symptoms [63, 64, (NSAIDS) can defer or prevent the onset of AD [84, 85]. 67, 68], cognitive impairment [63, 64], or visual halluci- Although subsequent clinical trials involving prednisol- nations [64, 68–70]. This disagreement arises in part, one and NSAIDS, such as the Alzheimer’s Disease due to the fact that most of these studies have small Anti-inflammatory Prevention Trial (ADAPT), failed to sample sizes or limited range of AD phonotypical pre- show improvement in cognitive decline in AD patients sentations. However, it is worth to mention that a or prevent AD progression in adults with a family well-powered multicenter study with a high sample size history of dementia , the difference between observa- has reported that the onset of symptoms and death in tional and randomised studies will need to be clarified in AD individuals with Lewy bodies occurs at younger ages future studies. as compared to those without Lewy bodies, and that AD Microglia, the resident phagocytes of the brain, plays individuals with Lewy bodies have higher chance to be an integral role in maintaining brain homeostasis and Gauthier et al. Translational Neurodegeneration (2018) 7:12 Page 4 of 7 protecting the brain from insults by mounting an innate tau may also trigger microglial activation . In pre- immune response when activated . Preclinical and clinical studies, reactive microglia are found to be suffi- post-mortem studies have consistently found that acti- cient in driving tau pathology and contribute to the vated microglia colocalises with Aβ plaque [88, 89], sug- spread of pathological tau in the brain . Microglia gesting a close intimate relationship between microglia have also been shown to internalize tau protein both in activation, Aβ and neuroinflammation. In AD, microglia vitro and in vivo. In post-mortem studies, microglia bind to soluble Aβ oligomers and fibrils via cell surface colocalise with various forms of tau in brain tissue of receptors, which triggers the activation of microglia . AD patients . A key issue is whether this response is adaptive or mal- Given the dynamic relationship between Aβ, tau and adaptive in nature. While acute microglia activation trig- microglia in AD, it is imperative to study the interplay gered by Aβ is aimed to eliminate Aβ aggregation via between these pathophysiologies so as to further under- phagocytosis, there is an inefficient clearance of Aβ pla- stand the sequence of events underlying the AD process. ques . Several mechanisms have been hypothesised, In this regard, studies that measure Aβ, tau, and neuro- including ongoing formation of Aβ and positive feedback inflammation concurrently will be of paramount import- loops between inflammation and amyloid precursor pro- ance. The findings of these studies will further broaden tein (APP) processing which compromise the cessation the A/T/N classification of individuals to include neuro- of neuroinflammation. Continued exposure to Aβ, che- inflammation biomarkers. mokines, cytokines, and inflammatory mediators leads to microglia being chronically activated at the Aβ plaque Conclusion site, which further contribute to Aβ production and ac- Towards an integration of the various pathological fac- cumulation in a vicious cycle. tors leading to targeted treatments. Microglia and neuroinflammation are also closely as- This expanded view of the pathological factors at play in sociated with tau in AD. Reactive microglia can produce persons with AD may be lead to therapeutic strategies t- inflammatory cytokines such as IL-1 which lead to an in- argeting the most active factors at a given time in each indi- crease in tau phosphorylation in neurons . This may vidual. We hope that meta-analysis of current observational contribute to the development of tau pathology and thus studies such as ADNI and others under development such accelerate the course of disease. Furthermore, misfolded as COMPASS-ND will facilitate the validation of various Table 1 Study of the various known pathological factors in AD Factor Imaging CSF Blood Potential RX Amyloid-β load [ C]PIB Amyloid-β(1–42) APP669–711; BACE inhibitors [ F]NAV4694 Amyloid-β(1–42); Amyloid-β [ F]florbetapir Amyloid-β(1–40); immunotherapy [ F]florbetaben [ F]flutemetamol Neurofibrillary tangles load [ F]MK6240 Phosphorylated tau The association of serum Anti-aggregation [ F]AV1451 phosphorylated Tau immunotherapy [ C]PBBB3 tau with tangles is unclear Neurodegeneration MRI Neurofilament light chain Neurofilament light chain Neurotrophic factors [ F]FDG (NFL); d neurogranin (Ng); (NFL) Visinin-like protein-1 (VILIP-1); Synaptosomal-associated protein 25 (SNAP-25); Neuron-specific enolase (NSE); Heart fatty acid binding protein (HFABP) Vascular load MRI CSF albumin /plasma albumin ratio Control of risk factors Lewy Body load NA α-synuclein α-synuclein α-synuclein immunotherapy Neuroinflammation Microglial Activation: Microglial Activation: Microglial Activation: NSAIDS activity [ C]PK11195 Chitinase-3-like protein 1 (YKL-40), Chitinase-3-like protein 1 Peroxisome proliferator- [ C]PBR28 soluble TREM2 (sTREM2) (YKL-40) activated receptor-γ [ C]DAA1106 Cytokines: Cytokines: (PPAR-γ) activators [ F] DPA714 TNF-α, IL-6, IL-1β TNF-α, IL-6, IL-1β, TNF-α inhibitor [ C] DPA713 Chemokines: monocyte Chemokines: monocyte [ F]GE180 chemotactic protein 1 [MCP-1] chemotactic protein 1 [MCP-1] Reactive astrocytes: [ C]L-des-deprenyl Gauthier et al. 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Published: May 31, 2018