Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

APOEGenotype, Family History of Dementia, and Alzheimer Disease Risk

APOEGenotype, Family History of Dementia, and Alzheimer Disease Risk BackgroundBoth family aggregation and apolipoprotein E (APOE) &epsiv;4 allele are well-known risk factors for dementia, but the relation between these two factors remains unclear.ObjectiveTo explore whether the risk of dementia and Alzheimer disease (AD) due to a positive family history is explained by APOEgenotypes.DesignCommunity-based cohort study.SettingThe Kungsholmen district of Stockholm, Sweden.ParticipantsA total of 907 nondemented people 75 years or older, followed up for 6 years to detect incident dementia and AD cases according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.Main Outcome MeasuresRisk of dementia and AD by Cox proportional hazards models after controlling for several potential confounders.ResultsSubjects who had at least 2 siblings with dementia were at an increased risk of AD. Individuals with both APOE&epsiv;4 allele and at least 2 affected first-degree relatives had a higher risk of dementia and AD compared with those without these 2 factors. Similar results were obtained for history of dementia separately in parents or siblings. Among the &epsiv;4 allele carriers, subjects with 2 or more first-degree demented relatives had increased risk of dementia and AD, whereas no increased risk was detected among non–&epsiv;4 carriers.ConclusionsFamily history of dementia was associated with an increased risk of dementia and AD in this very old population, but only among APOE&epsiv;4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE&epsiv;4 allele.The role of both family history of dementia and the apolipoprotein E (APOE) gene in the development of Alzheimer disease (AD) has been extensively investigated.There is strong evidence to suggest that APOE&epsiv;4 allele carriers, as well as subjects with a family history of dementia, have an increased risk of AD.Familial aggregation and genetic risk factors appear to be most influential in AD at relatively early ages.However, there are reports supporting an effect of both familial aggregation and APOE&epsiv;4 even in late-onset AD,although a lower effect in comparison with early-onset cases has been detected.It is hypothesized that APOE&epsiv;4 allele might explain the association between family history of dementia and AD. Previous studies have tried to evaluate this hypothesis, but to what extent familial aggregation is due to the association between the &epsiv;4 allele and AD remains equivocal. Some studies indicated that &epsiv;4-positive patients with AD tended to have a higher rate of family history of dementia than &epsiv;4-negative patients.Conversely, patients with family history of AD are also more likely to carry the &epsiv;4 allele than patients without family history.Other studies, however, showed that the APOE&epsiv;4 allele was not related to familial aggregation of AD.Most previous analyses have been hospital-based case-control studies. Because of ascertainment bias and severe truncation of data, these studies might overestimate the effects of family history and APOE&epsiv;4 allele, especially in very old people. Only a small-scale prospective study has examined both family history of dementia and APOE&epsiv;4 allele in relation to AD risk among people 75 years or older.In a previous study within the Kungsholmen Project, a strong familial aggregation was detected among prevalent cases of late-onset AD, but the contribution of the APOE&epsiv;4 allele was not considered.In the present study, we examined the 6-year follow-up data from the same project to explore whether the risk of dementia and AD due to a positive family history is explained by APOEgenotypes.METHODSSTUDY POPULATIONThe study base of the Kungsholmen Project included all registered residents 75 years or older of the Kungsholmen district of Stockholm, Sweden, in October 1987. A total of 1810 subjects (74.6% of the eligible subjects) participated in the baseline survey (1987-1989).Of the 1473 baseline participants who were diagnosed as being nondemented by a 2-phase design, 172 subjects were excluded because of refusal or moving at first follow-up (1991-1993). Of the remaining 1301 subjects who underwent the first follow-up evaluation, 176 did not provide information on family history and 218 had missing data on APOEgenotype. Therefore, the study population constituted 907 baseline nondemented individuals.At first follow-up, 167 persons received a dementia diagnosis, and 29 individuals refused to undertake the second follow-up. Thus, 526 non-demented alive subjects were further followed for another 3 years and examined during 1994 to 1996. For subjects who had died during the first (n = 185) and second (n = 122) follow-up periods, information regarding health status was obtained from medical records and death certificates.All phases of the project were approved by the Ethics Committee of the Karolinska Institutet, Stockholm.DIAGNOSIS OF INCIDENT DEMENTIA AND ADA standardized protocol was used at baseline and follow-ups, which included an interview on family and personal history, a clinical examination, and psychological tests. The diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Editioncriteriafollowing a 3-step diagnostic procedure used at the baseline survey.Our criteria for AD were similar to those of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Associationfor probable AD. The same diagnostic method was used for deceased subjects, based on the clinical records, discharge diagnoses, and death certificates.FAMILY HISTORY AND APOEGENOTYPEInformation on a history of dementia among first-degree relatives (ie, parents and siblings, not children) was obtained through a structured interview. For most subjects, multiple informants were sought to supplement and verify these responses. In our study, offspring were excluded because most offspring were too young to be at risk for dementia and AD. We accepted as “demented” only the family members reported as having both memory deficits and behavioral disturbances or time or space disorientation.The family history interview collected demographics for each first-degree relative and other information on family medical history. APOEgenotypes were determined by a standard procedure.COVARIATESData on demographics (age, sex, and education) and the number of siblings were collected at baseline interview. Educational levels were based on formal schooling. Information on vascular disorders at baseline, including heart disease (International Classification of Diseases, Eighth Revision,codes 410-414, 427, and 428), cerebrovascular disease (codes 430-438), and diabetes mellitus (code 250), were obtained from the computerized Stockholm Inpatient Register system that encompassed all hospitals in Stockholm since 1969.STATISTICAL ANALYSISWe used 1-way analysis of variance for the comparison of continuous variables and &khgr;2test for categorical variables. Several Cox proportional hazards models were constructed. First, we estimated the relative risk of dementia and AD associated with family history of dementia by different affected family members, controlling for age (in years), sex, education (<8 vs ≥8 years), number of siblings, vascular disease, and APOEgenotypes (categorized as &epsiv;2/&epsiv;2 or &epsiv;2/&epsiv;3, &epsiv;3/&epsiv;3, and any &epsiv;4). Then, as preliminary analysis showed similar dementia risk between subjects with none and 1 affected first-degree relative or sibling, these 2 categories were combined. In all succeeding analyses, we treated family history of dementia as a dichotomous variable (≥2 vs <2 demented relatives or siblings). We examined the combined effect between different affected family members and APOE&epsiv;4. On the basis of the hypothesis that APOE&epsiv;4 allele might modify the risk effect of family history on dementia, we conducted an analysis stratifying by APOE&epsiv;4 status. In addition, sensitivity analyses for the missing APOEgenotypes (n = 218) were performed by creating 2 extreme options. These analyses assumed that all subjects with missing values of APOEgenotypes had either no &epsiv;4 allele (option 1) or at least 1 &epsiv;4 allele (option 2).RESULTSAmong the 907 subjects, 265 developed dementia (203 with AD) during a mean follow-up of 5.1 years (SD, 2.1 years; maximum, 8.2 years). Table 1shows baseline characteristics of the study population by number of first-degree relatives with dementia. Overall, 31.1% (n = 282) of the study population reported a family history of dementia. No obvious group differences appeared for age, sex, education, Mini-Mental State Examination score, vascular disease, and family history of Parkinson disease. Subjects with a family history of dementia, compared with those without family history, had a higher mean number of siblings (F = 10.58, P<.001) and a slightly higher proportion of &epsiv;4 allele carriers (32.6% vs 25.6%; &khgr;2 = 4.78, P = .03).Table 1. Baseline Characteristics of 907 Participants by Number of First-Degree Relatives With DementiaCharacteristicsNo. of Relatives With Dementia01≥2No. of subjects (%)625 (68.9)200 (22.1)82 (9.0)Age, y, mean (SD)80.6 (4.7)80.1 (4.4)80.1 (3.7)Sex, No. (%) F471 (75.4)149 (74.5)68 (82.9)Education <8 y, No. (%)344 (55.2)*117 (58.8)†55 (67.1)No. of siblings, mean (SD)‡3.1 (2.2)3.6 (2.2)4.0 (2.1)Parkinson disease in any first-degree relatives, No. (%)25 (4.0)*11 (5.5)†5 (6.1)Vascular disease, No. (%)§131 (21.0)31 (15.5)12 (14.6)MMSE score, mean (SD)27.0 (2.3)27.1 (1.9)26.9 (2.0)APOEgenotype, No. (%) &epsiv;3/&epsiv;3377 (60.3)111 (55.5)42 (51.2) &epsiv;2/&epsiv;2 or &epsiv;2/&epsiv;388 (14.1)27 (13.5)10 (12.2) Any &epsiv;4160 (25.6)62 (31.0)30 (36.5)Abbreviations: APOE,apolipoprotein E; MMSE, Mini-Mental State Examination.*Data from 2 individuals were missing.†Data from 1 individual were missing.‡P<.001.§At least 1 of the following was present: heart disease, cerebrovascular disease, or diabetes mellitus.No significant difference was found in mean number of siblings, age at onset of dementia in first-degree relatives, age at death of parents, and birth order between nondemented subjects and those who became demented during the entire follow-up period.Subjects with 2 or more demented first-degree relatives had a nonsignificantly increased risk of dementia and AD, but subjects with at least 2 affected siblings had significantly increased risk of AD, which was still marginally significant when APOEgenotype was included in the model (Table 2).Table 2. RRs and 95% CIs of Dementia and AD Related to Familial AggregationNo. of Affected Family MembersNo. of SubjectsAll DementiasADNo. of CasesAdjusted RR (95% CI)*No. of CasesAdjusted RR (95% CI)*Parents and siblings  06251831.01391.0  1200510.8 (0.6-1.1)390.8 (0.6-1.2)  ≥282311.2 (0.8-1.8)251.3 (0.8-2.0)Parents 07642251.01721.0 ≥1143400.9 (0.7-1.3)311.0 (0.7-1.4)Siblings 07262091.01581.0 1136370.8 (0.6-1.1)290.8 (0.5-1.2) ≥245191.4 (0.9-2.3)161.7 (1.0-2.9)†Abbreviations: AD, Alzheimer disease; CI, confidence interval; RR, relative risk.*The RRs and 95% CIs were estimated after adjustment for age, sex, education, number of siblings, vascular disease, and apolipoprotein E genotype.†P=.04.The combined effect of family history of dementia and APOE&epsiv;4 allele was examined (Table 3). Subjects with both at least 2 affected first-degree relatives and APOE&epsiv;4 allele had a higher risk of dementia and AD than those in the reference group. The combined effects of either at least 1 parent or 2 siblings with dementia and APOE&epsiv;4 allele were similar to those in subjects with at least 2 first-degree relatives with dementia.Table 3. RRs and 95% CIs of Dementia and AD by Familial Aggregation and APOE&epsiv;4 AlleleFamily AggregationAPOE&epsiv;4No. of SubjectsAll DementiasADNo. of CasesAdjusted RR (95% CI)*No. of CasesAdjusted RR (95% CI)*≥2 Affected first-degree relatives NoNo6031601.01211.0 NoYes222741.5 (1.1-2.0)571.6 (1.2-2.2) YesNo52151.0 (0.6-1.7)111.0 (0.5-1.9) YesYes30162.6 (1.5-4.4)143.0 (1.7-5.3)≥1 Affected parent NoNo5641551.01161.0 NoYes200701.5 (1.1-2.0)561.7 (1.2-2.3) YesNo91200.8 (0.5-1.2)160.8 (0.5-1.4) YesYes52201.8 (1.2-3.0)152.0 (1.1-3.4)≥2 Affected siblings NoNo6291661.01261.0 NoYes233801.5 (1.2-2.0)611.6 (1.2-2.2) YesNo2691.2 (0.6-2.3)61.1 (0.5-2.6) YesYes19102.8 (1.5-5.4)103.9 (2.0-7.5)Abbreviations: AD, Alzheimer disease; APOE,apolipoprotein E; CI, confidence interval; RR, relative risk.*The RRs and 95% CIs were estimated after adjustment for age, sex, education, number of siblings, and vascular disease.Stratum-specific analysis by APOE&epsiv;4 status showed that the risks of dementia and AD for having at least 2 first-degree relatives or siblings were elevated only in the presence of APOE&epsiv;4 allele (Table 4).Table 4. RRs and 95% CIs of Dementia and AD Related to Familial Aggregation by APOE&epsiv;4 StatusNo. of SubjectsAll DementiasADNo. of CasesAdjusted RR (95% CI)*No. of CasesAdjusted RR (95% CI)*APOE&epsiv;4 Absent≥2 Affected first-degree relatives No6031601.01211.0 Yes52151.0 (0.6-1.7)111.0 (0.5-1.9)≥1 Affected parent No5641551.01161.0 Yes91200.8 (0.5-1.3)160.8 (0.5-1.4)≥2 Affected siblings No6291661.01261.0 Yes2691.2 (0.6-2.3)61.2 (0.5-2.7)APOE&epsiv;4 Present≥2 Affected first-degree relatives No222741.0571.0 Yes30161.9 (1.1-3.4)142.2 (1.2-4.1)≥1 Affected parent No200701.0561.0 Yes52201.3 (0.8-2.1)151.2 (0.7-2.2)≥2 Affected siblings No233801.0611.0 Yes19101.9 (1.0-3.8)102.6 (1.3-5.1)Abbreviations: AD, Alzheimer disease; APOE,apolipoprotein E; CI, confidence interval; RR, relative risk.*The RRs and 95% CIs were estimated after adjustment for age, sex, education, number of siblings, and vascular disease.Sensitivity analyses of missing APOEgenotypes led to results similar to those reported in Table 3and Table 4(data not shown).COMMENTIn this prospective community-based study, we found that a family history of dementia continued to influence the occurrence of dementia, and AD in particular, even after 75 years of age. Our data showed a combined effect of familial aggregation of dementia and APOE&epsiv;4 allele on the risk of dementia and AD. Subjects with 2 or more demented first-degree relatives or siblings had a substantially increased risk of dementia and AD only in the presence of APOE&epsiv;4 allele.A family history of dementia is generally considered an established risk factor for AD.However, several prospective studies, including a pooled analysis, did not find an association between family history of dementia and the risk of AD.By contrast, the present study showed that subjects with 2 or more demented siblings had increased risk of AD independent of several potential confounding factors. This indicates that the impact of a positive family history on dementia and AD persisted in this very old population. Our finding was in line with other earlier studies of AD,although the risk estimation is weaker than previously reported.Several studies suggested that susceptibility to AD was determined by interaction of APOEgenotypes with other genetic and environmental factors.One study found that individuals with APOE&epsiv;4 allele or a family history of dementia had a 9-fold increased age-specific risk of dementia than did those with neither of them.Another study demonstrated that family clustering of AD was due largely to factors other than APOEgenotype.In agreement with previous reports,our study showed that having both family history of dementia and APOE&epsiv;4 allele caused an increased risk of dementia and AD, particularly for subjects with either at least 1 parent or 2 first-degree relatives or siblings with dementia.In our study, positive family history of dementia, in the absence of APOE&epsiv;4 allele, was not associated with dementia and AD risk. On the contrary, other studies suggested that family history was a risk factor for dementia, independent of APOE&epsiv;4 allele.The effects of a family history on the development of dementia and AD among subjects with and without APOE&epsiv;4 allele may be age dependent. Our sample consisted of subjects with a minimum age of 75 years at entry. In addition, there were few subjects with 2 or more affected first-degree relatives or siblings and too few with dementia among the &epsiv;4-negative group. Thus, the statistical power may not be enough to detect a relevant association. An obvious familial aggregation observed only among the APOE&epsiv;4 carriers may suggest that there are some additional family-linked factors that may be active in the presence of APOE&epsiv;4 allele. This is consistent with the notion that the APOE&epsiv;4 allele is responsible for only a part of the familial risk. Therefore, other genetic or shared environmental factors need to be explored.There are several caveats to the interpretation of our results. First, misclassification in the assessment of dementia history in first-degree relatives might have occurred because of inaccurate reporting, especially concerning those of older relatives. However, information on family history was collected through multiple informants, which was shown to be reliable in other studies.Second, there may be a cohort effect for different risk estimates, in that parents would be less likely to be reported as having dementia than siblings because of lack of awareness of the disease when the parents were alive.To test this hypothesis, we analyzed the data separately for subjects with a history of dementia in different first-degree family members (either parent or siblings). The results showed that the relative risks were higher for affected siblings vs parents in our study. Furthermore, our results were similar to those from other studies.Third, it is reported that the impact of familial or genetic factors on AD and dementia diminishes with increasing age.Because of the old age of our study sample, the estimated relative risks in our study were lower than those of previous studies.Thus, our findings may not be generalizable to the younger-old population. Finally, we were concerned with the 17% of eligible subjects who did not undergo genotyping for APOE. To assess possible bias in the results due to the relatively high dropout rate of subjects with APOEgenotypes, 2 extreme situations were simulated in sensitivity analyses. The results did not show substantial difference from the original findings.In conclusion, our results suggested that family history of dementia and APOEgenotypes might still be involved in the development of dementia and AD among the very old. The effect of family history on dementia and AD was detectable only among subjects with the APOE&epsiv;4 allele. This implies that other familial (genetic or environmental) risk factors for dementia and AD might be active among APOE&epsiv;4 carriers.Correspondence:Chengxuan Qiu, MD, PhD, Stockholm Gerontology Research Center, Olivecronas väg 4, Box 6401, S-113 82 Stockholm, Sweden (chengxuan.qiu@neurotec.ki.se).Accepted for Publication:April 14, 2004.Author Contributions:Study concept and design: Huang, Qiu, von Strauss, Winblad, and Fratiglioni. Acquisition of data: von Strauss, Winblad, and Fratiglioni. Analysis and interpretation of data: Huang, Qiu, and Fratiglioni. Drafting of the manuscript: Huang, Qiu, and Fratiglioni. Critical revision of the manuscript for important intellectual content: Qiu, von Strauss, Winblad, and Fratiglioni. Statistical analysis: Huang, Qiu, and Fratiglioni. Obtained funding: Huang, Qiu, Winblad, and Fratiglioni. Administrative, technical, and material support: von Strauss, Winblad, and Fratiglioni. Study supervision: Qiu and Fratiglioni.Funding/Support:This study was supported by research grants from the Swedish Research Council, the Gun and Bertil Stohne Foundation, and the Gamla Tjänarinnor Foundation, Stockholm, and the Swedish Alzheimer Foundation, Lund.Acknowledgment:We thank our colleagues in the Kungsholmen Project study group for their cooperation in data collection and management.REFERENCESIMcDowellAlzheimer’s disease: insights from epidemiology.Aging (Milano)20011314316211442298GJarvikEBLarsonKGoddardInfluence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample.Am J Hum Genet1996581912008554056AJSlooterMCrustsSKalmijnRisk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study.Arch Neurol1998559649689678314CMvan DuijnPde KnijffMCrustsApolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease.Nat Genet1994774788075646LAFarrerLACupplesJLHainesEffects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis.JAMA1997278134913569343467CMvan DuijnDClaytonVChandraFamilial aggregation of Alzheimer’s disease and related disorders: a collaborative re-analysis of case-control studies.Int J Epidemiol199120(suppl 2)S13S201833349LFratiglioniAAhlbomMViitanenBWinbladRisk factors for late-onset Alzheimer’s disease: a population-based, case-control study.Ann Neurol1993332582668498809LJLaunerKAndersenMEDeweyRates and risk factors for dementia and Alzheimer’s disease: results from EURODEM pooled analyses.Neurology19995278849921852JMSilvermanGLiMLZaccarioPatterns of risk in first-degree relatives of patients with Alzheimer’s disease.Arch Gen Psychiatry1994515775868031231RDuaraWWBarkerRLopez-AlberolaAlzheimer’s disease: interaction of apolipoprotein E genotype, family history of dementia, gender, education, ethnicity, and age at onset.Neurology199646157515798649551GDeviROttmanMTangInfluence of APOE genotype on familial aggregation of AD in an urban population.Neurology19995378979410489042CBennettFCrawfordAOsborneEvidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer disease but is not causative.Am J Med Genet199560167485228RMayeuxYSternROttmanThe apolipoprotein &epsiv;4 allele in patients with Alzheimer’s disease.Ann Neurol1993347527548239575SDanetTBrousseauFRichardPAmouyelCBerrRisk of dementia in parents of probands with and without the apolipoprotein E4 allele: the EVA study.J Epidemiol Community Health19995339339810492731HPayamiHCrimslidBOkenA prospective study of cognitive health in the elderly: effects of family history and apolipoprotein E genotype.Am J Hum Genet1997609489569106542LFratiglioniMViitanenLBäkmanP-OSandmanBWinbladOccurrence of dementia in advanced age: the study design of the Kungsholmen Project.Neuroepidemiology199211(suppl 1)29361603245American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.Washington, DC: American Psychiatric Association; 1987:97-163LFratiglioniMGrutYForsellMViitanenBWinbladClinical diagnosis of Alzheimer’s disease and other dementias in a population survey: agreement and causes of disagreement in applying DSM-III-Rcriteria.Arch Neurol1992499279321520083GMcKhannDDrachmanMFolsteinRKatzmanDPriceEMStadlanClinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease.Neurology1984349399446610841SLTyasJManfredaLAStrainPRMontgomeryRisk factors for Alzheimer’s disease: a population-based, longitudinal study in Manitoba, Canada.Int J Epidemiol20013059059711416089JLindsayDLaurinRVerreaultRisk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging.Am J Epidemiol200215644545312196314LFarrerACupplesCMvan DuijnApolipoprotein E genotype in patients with Alzheimer’s disease: implications for the risk of dementia among relatives.Ann Neurol1995387978087486872RMayeuxROttmanGMaestreSynergistic effects of traumatic head injury and apolipoprotein-&epsiv;4 in patients with Alzheimer’s disease.Neurology1995455555577898715MMartinezDCampionABriceApolipoprotein E &epsiv;4 allele and familial aggregation of Alzheimer disease.Arch Neurol1998558108169626772DCSteffensBLPlassmanMJHelmsKAWelsh-BohmerTTNewmanJCSBreitnerAPOE and AD concordance in twin pairs as predictors of AD in first-degree relatives.Neurology20005459359810680788KMarderMXTangBAlfaroRisk of Alzheimer’s disease in relatives of Parkinson’s disease patients with and without dementia.Neurology19995271972410078716JMSilvermanCJSmithDBMarinRCMohsCBPropperFamilial patterns of risk in very late-onset Alzheimer disease.Arch Gen Psychiatry20036019019712578437 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Neurology American Medical Association

APOEGenotype, Family History of Dementia, and Alzheimer Disease Risk

Download PDF
5 pages

Loading next page...
 
/lp/american-medical-association/apoegenotype-family-history-of-dementia-and-alzheimer-disease-risk-KlpcOK4EK1

References (41)

Publisher
American Medical Association
Copyright
Copyright 2004 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6149
eISSN
2168-6157
DOI
10.1001/archneur.61.12.1930
pmid
15596614
Publisher site
See Article on Publisher Site

Abstract

BackgroundBoth family aggregation and apolipoprotein E (APOE) &epsiv;4 allele are well-known risk factors for dementia, but the relation between these two factors remains unclear.ObjectiveTo explore whether the risk of dementia and Alzheimer disease (AD) due to a positive family history is explained by APOEgenotypes.DesignCommunity-based cohort study.SettingThe Kungsholmen district of Stockholm, Sweden.ParticipantsA total of 907 nondemented people 75 years or older, followed up for 6 years to detect incident dementia and AD cases according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.Main Outcome MeasuresRisk of dementia and AD by Cox proportional hazards models after controlling for several potential confounders.ResultsSubjects who had at least 2 siblings with dementia were at an increased risk of AD. Individuals with both APOE&epsiv;4 allele and at least 2 affected first-degree relatives had a higher risk of dementia and AD compared with those without these 2 factors. Similar results were obtained for history of dementia separately in parents or siblings. Among the &epsiv;4 allele carriers, subjects with 2 or more first-degree demented relatives had increased risk of dementia and AD, whereas no increased risk was detected among non–&epsiv;4 carriers.ConclusionsFamily history of dementia was associated with an increased risk of dementia and AD in this very old population, but only among APOE&epsiv;4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE&epsiv;4 allele.The role of both family history of dementia and the apolipoprotein E (APOE) gene in the development of Alzheimer disease (AD) has been extensively investigated.There is strong evidence to suggest that APOE&epsiv;4 allele carriers, as well as subjects with a family history of dementia, have an increased risk of AD.Familial aggregation and genetic risk factors appear to be most influential in AD at relatively early ages.However, there are reports supporting an effect of both familial aggregation and APOE&epsiv;4 even in late-onset AD,although a lower effect in comparison with early-onset cases has been detected.It is hypothesized that APOE&epsiv;4 allele might explain the association between family history of dementia and AD. Previous studies have tried to evaluate this hypothesis, but to what extent familial aggregation is due to the association between the &epsiv;4 allele and AD remains equivocal. Some studies indicated that &epsiv;4-positive patients with AD tended to have a higher rate of family history of dementia than &epsiv;4-negative patients.Conversely, patients with family history of AD are also more likely to carry the &epsiv;4 allele than patients without family history.Other studies, however, showed that the APOE&epsiv;4 allele was not related to familial aggregation of AD.Most previous analyses have been hospital-based case-control studies. Because of ascertainment bias and severe truncation of data, these studies might overestimate the effects of family history and APOE&epsiv;4 allele, especially in very old people. Only a small-scale prospective study has examined both family history of dementia and APOE&epsiv;4 allele in relation to AD risk among people 75 years or older.In a previous study within the Kungsholmen Project, a strong familial aggregation was detected among prevalent cases of late-onset AD, but the contribution of the APOE&epsiv;4 allele was not considered.In the present study, we examined the 6-year follow-up data from the same project to explore whether the risk of dementia and AD due to a positive family history is explained by APOEgenotypes.METHODSSTUDY POPULATIONThe study base of the Kungsholmen Project included all registered residents 75 years or older of the Kungsholmen district of Stockholm, Sweden, in October 1987. A total of 1810 subjects (74.6% of the eligible subjects) participated in the baseline survey (1987-1989).Of the 1473 baseline participants who were diagnosed as being nondemented by a 2-phase design, 172 subjects were excluded because of refusal or moving at first follow-up (1991-1993). Of the remaining 1301 subjects who underwent the first follow-up evaluation, 176 did not provide information on family history and 218 had missing data on APOEgenotype. Therefore, the study population constituted 907 baseline nondemented individuals.At first follow-up, 167 persons received a dementia diagnosis, and 29 individuals refused to undertake the second follow-up. Thus, 526 non-demented alive subjects were further followed for another 3 years and examined during 1994 to 1996. For subjects who had died during the first (n = 185) and second (n = 122) follow-up periods, information regarding health status was obtained from medical records and death certificates.All phases of the project were approved by the Ethics Committee of the Karolinska Institutet, Stockholm.DIAGNOSIS OF INCIDENT DEMENTIA AND ADA standardized protocol was used at baseline and follow-ups, which included an interview on family and personal history, a clinical examination, and psychological tests. The diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Editioncriteriafollowing a 3-step diagnostic procedure used at the baseline survey.Our criteria for AD were similar to those of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Associationfor probable AD. The same diagnostic method was used for deceased subjects, based on the clinical records, discharge diagnoses, and death certificates.FAMILY HISTORY AND APOEGENOTYPEInformation on a history of dementia among first-degree relatives (ie, parents and siblings, not children) was obtained through a structured interview. For most subjects, multiple informants were sought to supplement and verify these responses. In our study, offspring were excluded because most offspring were too young to be at risk for dementia and AD. We accepted as “demented” only the family members reported as having both memory deficits and behavioral disturbances or time or space disorientation.The family history interview collected demographics for each first-degree relative and other information on family medical history. APOEgenotypes were determined by a standard procedure.COVARIATESData on demographics (age, sex, and education) and the number of siblings were collected at baseline interview. Educational levels were based on formal schooling. Information on vascular disorders at baseline, including heart disease (International Classification of Diseases, Eighth Revision,codes 410-414, 427, and 428), cerebrovascular disease (codes 430-438), and diabetes mellitus (code 250), were obtained from the computerized Stockholm Inpatient Register system that encompassed all hospitals in Stockholm since 1969.STATISTICAL ANALYSISWe used 1-way analysis of variance for the comparison of continuous variables and &khgr;2test for categorical variables. Several Cox proportional hazards models were constructed. First, we estimated the relative risk of dementia and AD associated with family history of dementia by different affected family members, controlling for age (in years), sex, education (<8 vs ≥8 years), number of siblings, vascular disease, and APOEgenotypes (categorized as &epsiv;2/&epsiv;2 or &epsiv;2/&epsiv;3, &epsiv;3/&epsiv;3, and any &epsiv;4). Then, as preliminary analysis showed similar dementia risk between subjects with none and 1 affected first-degree relative or sibling, these 2 categories were combined. In all succeeding analyses, we treated family history of dementia as a dichotomous variable (≥2 vs <2 demented relatives or siblings). We examined the combined effect between different affected family members and APOE&epsiv;4. On the basis of the hypothesis that APOE&epsiv;4 allele might modify the risk effect of family history on dementia, we conducted an analysis stratifying by APOE&epsiv;4 status. In addition, sensitivity analyses for the missing APOEgenotypes (n = 218) were performed by creating 2 extreme options. These analyses assumed that all subjects with missing values of APOEgenotypes had either no &epsiv;4 allele (option 1) or at least 1 &epsiv;4 allele (option 2).RESULTSAmong the 907 subjects, 265 developed dementia (203 with AD) during a mean follow-up of 5.1 years (SD, 2.1 years; maximum, 8.2 years). Table 1shows baseline characteristics of the study population by number of first-degree relatives with dementia. Overall, 31.1% (n = 282) of the study population reported a family history of dementia. No obvious group differences appeared for age, sex, education, Mini-Mental State Examination score, vascular disease, and family history of Parkinson disease. Subjects with a family history of dementia, compared with those without family history, had a higher mean number of siblings (F = 10.58, P<.001) and a slightly higher proportion of &epsiv;4 allele carriers (32.6% vs 25.6%; &khgr;2 = 4.78, P = .03).Table 1. Baseline Characteristics of 907 Participants by Number of First-Degree Relatives With DementiaCharacteristicsNo. of Relatives With Dementia01≥2No. of subjects (%)625 (68.9)200 (22.1)82 (9.0)Age, y, mean (SD)80.6 (4.7)80.1 (4.4)80.1 (3.7)Sex, No. (%) F471 (75.4)149 (74.5)68 (82.9)Education <8 y, No. (%)344 (55.2)*117 (58.8)†55 (67.1)No. of siblings, mean (SD)‡3.1 (2.2)3.6 (2.2)4.0 (2.1)Parkinson disease in any first-degree relatives, No. (%)25 (4.0)*11 (5.5)†5 (6.1)Vascular disease, No. (%)§131 (21.0)31 (15.5)12 (14.6)MMSE score, mean (SD)27.0 (2.3)27.1 (1.9)26.9 (2.0)APOEgenotype, No. (%) &epsiv;3/&epsiv;3377 (60.3)111 (55.5)42 (51.2) &epsiv;2/&epsiv;2 or &epsiv;2/&epsiv;388 (14.1)27 (13.5)10 (12.2) Any &epsiv;4160 (25.6)62 (31.0)30 (36.5)Abbreviations: APOE,apolipoprotein E; MMSE, Mini-Mental State Examination.*Data from 2 individuals were missing.†Data from 1 individual were missing.‡P<.001.§At least 1 of the following was present: heart disease, cerebrovascular disease, or diabetes mellitus.No significant difference was found in mean number of siblings, age at onset of dementia in first-degree relatives, age at death of parents, and birth order between nondemented subjects and those who became demented during the entire follow-up period.Subjects with 2 or more demented first-degree relatives had a nonsignificantly increased risk of dementia and AD, but subjects with at least 2 affected siblings had significantly increased risk of AD, which was still marginally significant when APOEgenotype was included in the model (Table 2).Table 2. RRs and 95% CIs of Dementia and AD Related to Familial AggregationNo. of Affected Family MembersNo. of SubjectsAll DementiasADNo. of CasesAdjusted RR (95% CI)*No. of CasesAdjusted RR (95% CI)*Parents and siblings  06251831.01391.0  1200510.8 (0.6-1.1)390.8 (0.6-1.2)  ≥282311.2 (0.8-1.8)251.3 (0.8-2.0)Parents 07642251.01721.0 ≥1143400.9 (0.7-1.3)311.0 (0.7-1.4)Siblings 07262091.01581.0 1136370.8 (0.6-1.1)290.8 (0.5-1.2) ≥245191.4 (0.9-2.3)161.7 (1.0-2.9)†Abbreviations: AD, Alzheimer disease; CI, confidence interval; RR, relative risk.*The RRs and 95% CIs were estimated after adjustment for age, sex, education, number of siblings, vascular disease, and apolipoprotein E genotype.†P=.04.The combined effect of family history of dementia and APOE&epsiv;4 allele was examined (Table 3). Subjects with both at least 2 affected first-degree relatives and APOE&epsiv;4 allele had a higher risk of dementia and AD than those in the reference group. The combined effects of either at least 1 parent or 2 siblings with dementia and APOE&epsiv;4 allele were similar to those in subjects with at least 2 first-degree relatives with dementia.Table 3. RRs and 95% CIs of Dementia and AD by Familial Aggregation and APOE&epsiv;4 AlleleFamily AggregationAPOE&epsiv;4No. of SubjectsAll DementiasADNo. of CasesAdjusted RR (95% CI)*No. of CasesAdjusted RR (95% CI)*≥2 Affected first-degree relatives NoNo6031601.01211.0 NoYes222741.5 (1.1-2.0)571.6 (1.2-2.2) YesNo52151.0 (0.6-1.7)111.0 (0.5-1.9) YesYes30162.6 (1.5-4.4)143.0 (1.7-5.3)≥1 Affected parent NoNo5641551.01161.0 NoYes200701.5 (1.1-2.0)561.7 (1.2-2.3) YesNo91200.8 (0.5-1.2)160.8 (0.5-1.4) YesYes52201.8 (1.2-3.0)152.0 (1.1-3.4)≥2 Affected siblings NoNo6291661.01261.0 NoYes233801.5 (1.2-2.0)611.6 (1.2-2.2) YesNo2691.2 (0.6-2.3)61.1 (0.5-2.6) YesYes19102.8 (1.5-5.4)103.9 (2.0-7.5)Abbreviations: AD, Alzheimer disease; APOE,apolipoprotein E; CI, confidence interval; RR, relative risk.*The RRs and 95% CIs were estimated after adjustment for age, sex, education, number of siblings, and vascular disease.Stratum-specific analysis by APOE&epsiv;4 status showed that the risks of dementia and AD for having at least 2 first-degree relatives or siblings were elevated only in the presence of APOE&epsiv;4 allele (Table 4).Table 4. RRs and 95% CIs of Dementia and AD Related to Familial Aggregation by APOE&epsiv;4 StatusNo. of SubjectsAll DementiasADNo. of CasesAdjusted RR (95% CI)*No. of CasesAdjusted RR (95% CI)*APOE&epsiv;4 Absent≥2 Affected first-degree relatives No6031601.01211.0 Yes52151.0 (0.6-1.7)111.0 (0.5-1.9)≥1 Affected parent No5641551.01161.0 Yes91200.8 (0.5-1.3)160.8 (0.5-1.4)≥2 Affected siblings No6291661.01261.0 Yes2691.2 (0.6-2.3)61.2 (0.5-2.7)APOE&epsiv;4 Present≥2 Affected first-degree relatives No222741.0571.0 Yes30161.9 (1.1-3.4)142.2 (1.2-4.1)≥1 Affected parent No200701.0561.0 Yes52201.3 (0.8-2.1)151.2 (0.7-2.2)≥2 Affected siblings No233801.0611.0 Yes19101.9 (1.0-3.8)102.6 (1.3-5.1)Abbreviations: AD, Alzheimer disease; APOE,apolipoprotein E; CI, confidence interval; RR, relative risk.*The RRs and 95% CIs were estimated after adjustment for age, sex, education, number of siblings, and vascular disease.Sensitivity analyses of missing APOEgenotypes led to results similar to those reported in Table 3and Table 4(data not shown).COMMENTIn this prospective community-based study, we found that a family history of dementia continued to influence the occurrence of dementia, and AD in particular, even after 75 years of age. Our data showed a combined effect of familial aggregation of dementia and APOE&epsiv;4 allele on the risk of dementia and AD. Subjects with 2 or more demented first-degree relatives or siblings had a substantially increased risk of dementia and AD only in the presence of APOE&epsiv;4 allele.A family history of dementia is generally considered an established risk factor for AD.However, several prospective studies, including a pooled analysis, did not find an association between family history of dementia and the risk of AD.By contrast, the present study showed that subjects with 2 or more demented siblings had increased risk of AD independent of several potential confounding factors. This indicates that the impact of a positive family history on dementia and AD persisted in this very old population. Our finding was in line with other earlier studies of AD,although the risk estimation is weaker than previously reported.Several studies suggested that susceptibility to AD was determined by interaction of APOEgenotypes with other genetic and environmental factors.One study found that individuals with APOE&epsiv;4 allele or a family history of dementia had a 9-fold increased age-specific risk of dementia than did those with neither of them.Another study demonstrated that family clustering of AD was due largely to factors other than APOEgenotype.In agreement with previous reports,our study showed that having both family history of dementia and APOE&epsiv;4 allele caused an increased risk of dementia and AD, particularly for subjects with either at least 1 parent or 2 first-degree relatives or siblings with dementia.In our study, positive family history of dementia, in the absence of APOE&epsiv;4 allele, was not associated with dementia and AD risk. On the contrary, other studies suggested that family history was a risk factor for dementia, independent of APOE&epsiv;4 allele.The effects of a family history on the development of dementia and AD among subjects with and without APOE&epsiv;4 allele may be age dependent. Our sample consisted of subjects with a minimum age of 75 years at entry. In addition, there were few subjects with 2 or more affected first-degree relatives or siblings and too few with dementia among the &epsiv;4-negative group. Thus, the statistical power may not be enough to detect a relevant association. An obvious familial aggregation observed only among the APOE&epsiv;4 carriers may suggest that there are some additional family-linked factors that may be active in the presence of APOE&epsiv;4 allele. This is consistent with the notion that the APOE&epsiv;4 allele is responsible for only a part of the familial risk. Therefore, other genetic or shared environmental factors need to be explored.There are several caveats to the interpretation of our results. First, misclassification in the assessment of dementia history in first-degree relatives might have occurred because of inaccurate reporting, especially concerning those of older relatives. However, information on family history was collected through multiple informants, which was shown to be reliable in other studies.Second, there may be a cohort effect for different risk estimates, in that parents would be less likely to be reported as having dementia than siblings because of lack of awareness of the disease when the parents were alive.To test this hypothesis, we analyzed the data separately for subjects with a history of dementia in different first-degree family members (either parent or siblings). The results showed that the relative risks were higher for affected siblings vs parents in our study. Furthermore, our results were similar to those from other studies.Third, it is reported that the impact of familial or genetic factors on AD and dementia diminishes with increasing age.Because of the old age of our study sample, the estimated relative risks in our study were lower than those of previous studies.Thus, our findings may not be generalizable to the younger-old population. Finally, we were concerned with the 17% of eligible subjects who did not undergo genotyping for APOE. To assess possible bias in the results due to the relatively high dropout rate of subjects with APOEgenotypes, 2 extreme situations were simulated in sensitivity analyses. The results did not show substantial difference from the original findings.In conclusion, our results suggested that family history of dementia and APOEgenotypes might still be involved in the development of dementia and AD among the very old. The effect of family history on dementia and AD was detectable only among subjects with the APOE&epsiv;4 allele. This implies that other familial (genetic or environmental) risk factors for dementia and AD might be active among APOE&epsiv;4 carriers.Correspondence:Chengxuan Qiu, MD, PhD, Stockholm Gerontology Research Center, Olivecronas väg 4, Box 6401, S-113 82 Stockholm, Sweden (chengxuan.qiu@neurotec.ki.se).Accepted for Publication:April 14, 2004.Author Contributions:Study concept and design: Huang, Qiu, von Strauss, Winblad, and Fratiglioni. Acquisition of data: von Strauss, Winblad, and Fratiglioni. Analysis and interpretation of data: Huang, Qiu, and Fratiglioni. Drafting of the manuscript: Huang, Qiu, and Fratiglioni. Critical revision of the manuscript for important intellectual content: Qiu, von Strauss, Winblad, and Fratiglioni. Statistical analysis: Huang, Qiu, and Fratiglioni. Obtained funding: Huang, Qiu, Winblad, and Fratiglioni. Administrative, technical, and material support: von Strauss, Winblad, and Fratiglioni. Study supervision: Qiu and Fratiglioni.Funding/Support:This study was supported by research grants from the Swedish Research Council, the Gun and Bertil Stohne Foundation, and the Gamla Tjänarinnor Foundation, Stockholm, and the Swedish Alzheimer Foundation, Lund.Acknowledgment:We thank our colleagues in the Kungsholmen Project study group for their cooperation in data collection and management.REFERENCESIMcDowellAlzheimer’s disease: insights from epidemiology.Aging (Milano)20011314316211442298GJarvikEBLarsonKGoddardInfluence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample.Am J Hum Genet1996581912008554056AJSlooterMCrustsSKalmijnRisk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study.Arch Neurol1998559649689678314CMvan DuijnPde KnijffMCrustsApolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease.Nat Genet1994774788075646LAFarrerLACupplesJLHainesEffects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis.JAMA1997278134913569343467CMvan DuijnDClaytonVChandraFamilial aggregation of Alzheimer’s disease and related disorders: a collaborative re-analysis of case-control studies.Int J Epidemiol199120(suppl 2)S13S201833349LFratiglioniAAhlbomMViitanenBWinbladRisk factors for late-onset Alzheimer’s disease: a population-based, case-control study.Ann Neurol1993332582668498809LJLaunerKAndersenMEDeweyRates and risk factors for dementia and Alzheimer’s disease: results from EURODEM pooled analyses.Neurology19995278849921852JMSilvermanGLiMLZaccarioPatterns of risk in first-degree relatives of patients with Alzheimer’s disease.Arch Gen Psychiatry1994515775868031231RDuaraWWBarkerRLopez-AlberolaAlzheimer’s disease: interaction of apolipoprotein E genotype, family history of dementia, gender, education, ethnicity, and age at onset.Neurology199646157515798649551GDeviROttmanMTangInfluence of APOE genotype on familial aggregation of AD in an urban population.Neurology19995378979410489042CBennettFCrawfordAOsborneEvidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer disease but is not causative.Am J Med Genet199560167485228RMayeuxYSternROttmanThe apolipoprotein &epsiv;4 allele in patients with Alzheimer’s disease.Ann Neurol1993347527548239575SDanetTBrousseauFRichardPAmouyelCBerrRisk of dementia in parents of probands with and without the apolipoprotein E4 allele: the EVA study.J Epidemiol Community Health19995339339810492731HPayamiHCrimslidBOkenA prospective study of cognitive health in the elderly: effects of family history and apolipoprotein E genotype.Am J Hum Genet1997609489569106542LFratiglioniMViitanenLBäkmanP-OSandmanBWinbladOccurrence of dementia in advanced age: the study design of the Kungsholmen Project.Neuroepidemiology199211(suppl 1)29361603245American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.Washington, DC: American Psychiatric Association; 1987:97-163LFratiglioniMGrutYForsellMViitanenBWinbladClinical diagnosis of Alzheimer’s disease and other dementias in a population survey: agreement and causes of disagreement in applying DSM-III-Rcriteria.Arch Neurol1992499279321520083GMcKhannDDrachmanMFolsteinRKatzmanDPriceEMStadlanClinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease.Neurology1984349399446610841SLTyasJManfredaLAStrainPRMontgomeryRisk factors for Alzheimer’s disease: a population-based, longitudinal study in Manitoba, Canada.Int J Epidemiol20013059059711416089JLindsayDLaurinRVerreaultRisk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging.Am J Epidemiol200215644545312196314LFarrerACupplesCMvan DuijnApolipoprotein E genotype in patients with Alzheimer’s disease: implications for the risk of dementia among relatives.Ann Neurol1995387978087486872RMayeuxROttmanGMaestreSynergistic effects of traumatic head injury and apolipoprotein-&epsiv;4 in patients with Alzheimer’s disease.Neurology1995455555577898715MMartinezDCampionABriceApolipoprotein E &epsiv;4 allele and familial aggregation of Alzheimer disease.Arch Neurol1998558108169626772DCSteffensBLPlassmanMJHelmsKAWelsh-BohmerTTNewmanJCSBreitnerAPOE and AD concordance in twin pairs as predictors of AD in first-degree relatives.Neurology20005459359810680788KMarderMXTangBAlfaroRisk of Alzheimer’s disease in relatives of Parkinson’s disease patients with and without dementia.Neurology19995271972410078716JMSilvermanCJSmithDBMarinRCMohsCBPropperFamilial patterns of risk in very late-onset Alzheimer disease.Arch Gen Psychiatry20036019019712578437

Journal

JAMA Neurology – American Medical Association

Published: Dec 1, 2004

There are no references for this article.