Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Neurol. Author manuscript; available in PMC 2011 December 1.
Published in final edited form as:
PMCID: PMC3048805

Meta-Analysis confirms CR1, CLU, and PICALM as Alzheimer’s disease risk loci and reveals interactions with APOE genotypes



To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer’s disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes.


Association study of AD and CLU, PICALM, CR1 and APOE genotypes.


Academic research institutions in the United States, Canada, and Israel.


7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively normal controls, 1,092 with autopsies from 12 different studies, including Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.


Unadjusted, CLU [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85 – 0.96 for single nucleotide polymorphism (SNP) rs11136000], CR1 (OR = 1.14, CI = 1.07 – 1.22, SNP rs3818361), and PICALM (OR = 0.89, CI = 0.84 – 0.94, SNP rs3851179) were associated with AD in Caucasians. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least one APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, APOE ε4 (+/−), and an interaction term showed significant interaction between APOE ε4 (+/−) and PICALM.


We confirm in a completely independent dataset that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subject. Thus, APOE and PICALM synergistically interact.


Alzheimer’s disease (AD) is the most common form of dementia, affecting 5% of the population over 65 years and 30–50% over 80 years. Substantial progress was made identifying genes for rare forms of early-onset AD14 and this early success significantly contributed to biologic study on AD mechanisms and more recently multiple drug discovery approaches. Late-onset AD, the common form of the disease, has been more difficult to solve with apolipoprotein E (APOE) being the only confirmed susceptibility locus5. The combination of high-density genotyping methods, large well-characterized AD and control populations, and statistical methods to evaluate population stratification now provide the tools to identify additional genes contributing to AD risk.

Recently, two genome-wide association studies (GWAS) reported evidence that variations in CLU (encoding Clusterin), PICALM (encoding the Phosphatidylinositol Binding Clathrin Assembly protein), and CR1 (encoding Complement Component (3b/4b) Receptor 1), confer genetic risk for AD67. Evidence for these three loci reached genome wide significance in samples consisting of 5,964 cases and 10,188 controls (PICALM and CLU) and 5,887 cases and 8,508 controls (CRI and CLU). To analyze the role of these genes in AD risk, the Alzheimer’s Disease Genetics Consortium (ADGC) performed a meta analysis using GWAS data for 15,239 subjects from 9 Northern European Whites cohorts and 5 cohorts that included African Americans, Israeli Arabs, and Caribbean Hispanics (Table 1). Genotypes for CR1, CLU, and PICALM were analyzed for association with AD using cohorts that are completely independent of those originally used to identify these 3 loci as AD susceptibility factors. The controls used are all elderly (age > 60 years). We also examined the interaction of APOE with CR1, CLU, and PICALM on AD risk.

Table 1
Sample Description



All cohorts are described in more detail in the supplementary material provide online. The National Institute on Aging (NIA) Alzheimer’s Disease Center (ADC) subjects were ascertained, evaluated, and sampled by the clinical and neuropathology cores of the 29 NIA-funded ADCs (Table 1). Subject data data collection is coordinated by the National Alzheimer’s Coordinating Center (NACC). DNA from these samples for genotyping was prepared by the National Cell Repository for Alzheimer’s Disease (NCRAD). The Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects are AD cases and controls ascertained for neuroimaging, biomarker, and genetic studies. Data used here were generates as previously described8 and obtained from the ADNI database ( ). The Collaborative Aging and Memory Project (CAMP) subjects are from the Amish communities of central Ohio and northern Indiana910. The Columbia University (CU) subjects are a Hispanic cohort described in detail elsewhere11. The Framingham Heart Study (FHS) is a single-site, community-based, ongoing cohort study described elsewhere1214. Phenotype and genome-wide association study (GWAS) data were from dbGaP website ( The Johns Hopkins University (JHU) subjects are from the Genetic and Environmental Risk Factors for Alzheimer’s disease among African Americans (GenerAAtions) Study identified through the electronic claims database of the Henry Ford Health System. The MIRAGE Study is a family-based genetic epidemiological study of AD in which AD cases and unaffected sibling controls were enrolled at 17 clinical centers in the United States, Canada, Germany, and Greece15. The NIA-LOAD Family Study16 cohort are families with two or more affected siblings with LOAD and unrelated, non-demented control subjects similar in age and ethnic background. One case per family was selected and controls were deteremined to be cognitively normal after an in-person neurological examination and were not related to a study participant. The Oregon Health and Science University (OHSU) were recruited from aging research cohorts at 10 NIA-funded ADCs and do not overlap with other ADGC samples. The TGEN dataset is a publicly available sample of AD cases and controls ( The University of Miami/Vanderbilt University/Mt. Sinai School of Medicine (UM/VU/MSSM) were new and previously published1822 subjects ascertained at the University of Miami, Vanderbilt University and Mt. Sinai School of Medicine. The Wadi Ara dataset are from an inbred Arab community in northern Israel2326.


The cohorts used were genotyped either on Illumina or Affymetrix SNP arrays (Table 2). We selected 17 SNPs from CR1, CLU, and PICALM that were recently reported to be significantly associated with AD in two large GWA studies67 (Table 3). Additional genotypes were obtained using an Applied Biosystems’ (ABI) TaqMan Assays including genotypes for rs7982. Genotyping for the APOE ε2/ε3/ε4 alleles was performed as described in the supplementary material provided online.

Table 2
GWAS genotyping platform, numbers of SNPs genotyped and imputed, and APOE genotype distribution for the study samples
Table 3
Meta-analysis results for association of AD with SNPs in CR1, CLU, and PICALM in Caucasians


The analysis included only individuals with a censoring age of 60 years or older. The age used for cases was that most closely approximating the age of disease onset. For some cohorts, age-at-onset was ascertained while for others, only age-at-ascertainment was available. For some autopsied subjects, only age-at-death was available and was used as the censoring age. For all studies, the age used for controls was the age of last exam or death. (see also supplementary material provided online).

Imputation procedure

We imputed genotypes for all SNPs within 10Kb of the three genes using the Markov Chain haplotyping (MaCH) software27 to obtain a common set of SNPs across all datasets. We imputed SNPs from both HapMap releases II and III and retained those with pairwise linkage disequilibrium (LD; r2 > 0.50) for further analysis (see also the supplementary material online for more detail and for data cleaning protocols).

Population Substructure

To determine if population substructure existed in the different datasets, we used 30,000 – 100,000 SNPs with minor allele frequency (MAF) > 0.25 and minimal between-SNP linkage disequilibrium (r2 < 0.20) sampled at random from the autosomes, and analyzed with the STRUCTURE software package2829. To account for population substructure in association analyses, EIGENSTRAT30 was used on each cohort to generate loadings from principal components analysis on the sampled SNPs sampled (see also supplementary material online).

Statistical Analysis

Genotyped and imputed SNPs were tested for association with AD using a logistic generalized linear model (GLM) in case-control datasets and a logistic generalized estimating equation (GEE) in family-based datasets. Genotyped SNPs were coded as 0, 1, or 2 according to the number of minor alleles under the additive genetic model, whereas APOE was coded as 0 or 1 according to the presence or absence of the ε4 allele. For imputed SNPs, a quantitative estimate between 0 and 2 for the dose of the minor allele were used to incorporate the uncertainty of the imputation estimates. Regression models for each SNP without covariates were evaluated for comparison with results from the original reports67 Additional models containing all permutations of covariates for age, gender and APOE ε4 status were also tested. Formal tests of interaction between the SNPs and APOE were assessed by including the main effects and an interaction term. Regression models were evaluated using the R package31. Heterogeneity among odds ratios was assessed using Cochran’s Q, which was calculated as the weighted sum of squared differences between individual study effects and the pooled effect across studies, with the weights being those used in the pooling method. Q is distributed as a χ2 with k (number of studies) minus 1 degrees of freedom. The I2 statistic3233 describes the percentage of variation across studies that is due to heterogeneity rather than chance and is calculated as follows: I2 = 100% × (Q−df)/Q. I2 is an intuitive and simple expression of the inconsistency of studies’ results. Unlike Q it does not inherently depend upon the number of studies considered. SNP association results obtained from individual datasets were combined by meta-analysis using the inverse variance method implemented in the software package METAL ( An additive model was assumed and the association results across datasets were combined by summing the regression coefficients weighted by the inverse variance of the coefficients. The meta-analysis P-value of the association was estimated by the summarized test statistic.


To analyze the role CR1, CLU, and PICALM in AD risk, the ADGC performed a meta-analysis using phenotypes and GWAS data from 12 different cohorts (Table 1). The ADGC is a collaborative network in the United States that includes the 29 NIA-funded ADCs and numerous AD genetics investigators who are working to identify genes responsible for AD. Of 7,070 AD cases examined, 3,055 of had autopsy documentation of AD. Of the 8,169 cognitively normal elderly subjects (age >60) examined, 1,155 had autopsies documenting absence of significant AD neuropathology. The cohorts used included unrelated Caucasian cases and controls from the following sources: the NIA-funded ADCs, ADNI8, 34, UM/VU/MSSM1821, TGEN17, and OHSU35. Caucasian cases and controls from the following family-based studies were also included: the MIRAGE Study15, FHS1314, 36, NIA-LOAD, and CAMP910. Populations not of Caucasian descent included African American subjects from several ADCs, a community-based (Detroit) study of AD, and the MIRAGE study15; Caribbean Hispanics from Manhattan, the Dominican Republic, and Puerto Rico; and members of a genetically isolated Arab community in Wadi Ara, Israel2326.

In each dataset, we evaluated association of AD with SNPs in or near CR1, CLU, and PICALM that were genotyped on various platforms or imputed (Table 2). Results were combined across datasets using a meta-analysis approach (Table 3). We analyzed each racial/ethnic group separately. In Caucasians, the largest group (n = 5,935 cases, 7,034 controls), we found significant evidence of association with multiple SNPs at each locus. In the unadjusted analyses, we obtained an odds ratio (OR) of 0.91 with a 95% confidence interval (CI) of (0.85 – 0.96) for CLU SNP rs11136000, which is comparable to the effect-size reported previously for the same SNP (ORs = 0.867 and 0.916). For the CR1 SNP rs3818361, we obtained an OR of 1.14 (CI = 1.07 – 1.22) compared to the previous report of 1.197. PICALM SNP rs3851179 had an OR of 0.89 (CI = 0.84 – 0.94) compared to 0.86 observed previously6. None of the SNPs were significantly associated with AD in any of the other ethnic groups analyzed together or separately, possibly due to small sizes of these groups (1,135 cases and 1,135 controls, Supplementary eTable 1).

We also examined the influence of APOE on the associations of the three genes with AD, since APOE is a known AD susceptibility locus in most ethnic groups5, 37 and several APOE genotypes have been reported to modify disease expression in persons with rare mutations in presenilin 1 (PSEN1)38, presenilin 2 (PSEN2)39, and the amyloid precursor protein (APP)3940 genes. For the 13 cohorts where APOE genotype data were available, presence of one or more APOE ε4 alleles was significantly associated with AD (ORs ranging from 1.80 to 9.05) in all groups except the Amish and Israeli-Arabs (Table 4). We next re-evaluated the association of AD with the CR1, CLU and PICALM SNPs in the Caucasian cohorts adjusting for age, sex, and the presence of at least one APOE ε4 allele and found greatly reduced evidence for association with PICALM after adjustment (Table 3, Supplementary eTable 2), an effect that is attributable primarily to APOE (eTable 2). To explore this effect further, we analyzed the association of CR1, CLU, and PICALM SNPs with AD in subgroups stratified by the presence (+) or absence (−) of the APOE ε4 allele. This analysis revealed that the association with CLU is evident only among ε4 (−) subjects, whereas the association with PICALM is evident only among ε4 (+) subjects (Table 5). Analysis of models containing terms for the main effects of each SNP and APOE ε4 (+/−), and an interaction term showed significant evidence of interaction for APOE ε4 (+/−) and seven of the nine PICALM SNPs with indications of a synergistic effect of these two genes on AD risk (Table 5 and Supplementary eTable 3). Interactions of CR1 and CLU SNPs with APOE ε4 (+/−) were not statistically significant.

Table 4
APOE genotype and allele frequencies, and odds ratios for association of ε4 with Alzheimer’s Disease
Table 5
Association of AD with CR1, CLU, and PICALM SNPs stratified by APOE ε4 carrier status and testing statistical interaction with APOE ε4 carrier status in Caucasian ...


Using a large multi-center dataset of AD cases and controls, we confirm that CR1, CLU and PICALM are AD susceptibility loci in European ancestry populations. The ORs we get for each is similar to those obtained in the original discovery cohort, suggesting that these estimates of risk are quite accurate for the Caucasian AD population, reflecting in part the large size of the cohorts used67. Clearly a large dataset is required to replicate these small-effect loci. We were unable to replicate the association of these 3 genes in the African-American, Arab, and Hispanic populations. However, further analysis is merited in these racial/ethnic groups using larger cohorts.

While this manuscript was being prepared for publication, a GWAS on AD was reported by Seshadri et al.41. There was some overlap in that study and ours in that the TGEN and Framingham cohorts are used in both studies. However, whereas Seshadri et al. used only prospectively diagnosed AD cases (n=52) and unrelated controls (n=2,091) from the Framingham Study, we included these subjects as well as prevalent and newly diagnosed cases and related controls yielding a total sample of 197 AD cases and 2,392 controls. Both studies independently confirm that CLU and PICALM are AD susceptibility genes. A primary difference between the 2 studies is that here we confirm CR1 as an AD locus while Seshadri et al.41 obtained only nominal support for CR1.

The cohorts used here have several features worth mentioning in the context of GWAS for AD. First, the cohorts have a large number of autopsies in the cases (3,055). Because the gold standard for diagnosis is neuropathologic confirmation of AD pathology, using autopsied cases reduces etiologic heterogeneity. Second, the controls used here were elderly, of comparable age to case onset ages, and were cognitively normal. Since these subjects lived to a comparable age to cases without developing AD, the case-control contrast should be more robust than if young controls are used. In addition, cases and controls will be comparably censored at other non-AD loci responsible for common diseases of the elderly that are unrelated to AD. Third, the cohorts used here were not involved in the initial discovery of CLU, CR1 and PICALM and thus represent a completely independent replication dataset. This is critical in terms of evaluating evidence that these genes are truly AD risk loci. The ideal controls for an AD GWAS would be subjects who were cognitively normal at death, had autopsy documentation that plaque load and tangle distribution did not reach criteria for AD pathology, and who were elderly. In autopsy series of older cognitively normal subjects, most have some NFTs and some non-neuritic, and possibly spare neuritic amyloid deposits, but do not reach the accepted threshold for AD, although about a third of these normal subjects do meet neuropathologic criteria for AD4245. In autopsy series of MCI subjects, up to two thirds of subjects have AD-level neuropathology46. These findings give rise to the hypothesis that amyloid deposition and tangle formation begin before cognitive decline becomes detectable, an idea strengthened by recent biomarker and amyloid imaging work47. Thus in persons without dementia, a fraction, mostly those with MCI, will develop AD within a few years and this conversion rate increases with the age of the population, decreasing the contrast between cases and controls and reducing power. To minimize the potential confounding effect of MCI, we excluded them from these analyses and emphasized 1,155 controls with autopsy information (Table 1).

When we examined the interaction CR1, CLU and PICALM, and APOE genotypes, we detected synergy between APOE and PICALM but not with CR1 or CLU. Our results show that the PICALM association is predominantly in subjects carrying the APOE ε4 allele. Consistent with conclusions from previous studies showing interaction of APOE with PSEN138, PSEN239, and APP3940, our results suggest that the APOE and PICALM gene products participate in a common pathogenic pathway leading to AD. Since PSEN1, PSEN2, and APP are all involved in Aβ production, PICALM may also participate in this process though a more indirect involvement cannot be ruled out and the biology of these interactions remains to be detemined. We did not detect an interaction of APOE with CR1 or CLU, though this could be due to sample size, which was not large enough to detect very weak interactions. Also, since the APOE effect on AD risk is much stronger in young case populations37, the age structure of our study and of others may not be optimal for detecting these interactions.

Our study and those from other consortia6,7,56 show that AD susceptibility loci can be identified by GWAS. Initial AD GWAS had samples sizes that, in comparison to those from the large consortia, were modest and inadequately powered to detect the small effect loci replicated here19, 4853. As sample sizes increase, as in other complex disorders, we expect additional loci to be identified.

Supplementary Material

Supplementary Tables

Supplementary Text


The Alzheimer’s Disease Genetics Consortium is funded by the U.S. National Institutes of Health, National Institute on Aging (NIH-NIA) grants U01-AG032984 and RC2-AG036528 and a grant from a private foundation wishing to remain anonymous. The NIH-NIA also provides financial support to NACC (U01-AG016976), NCRAD (U24-AG021886), and the Alzheimer’s Disease Centers: Banner Alzheimer’s Institute (P30 AG019610), Boston University (P30 AG013846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, R01 MH080295), Columbia University (P50 AG008702), Duke University (P30 AG028377), Emory University (AG025688), Indiana University (P30 AG10133), Johns Hopkins University (P50 AG005146), Massachusetts General Hospital (P50 AG005134), Mayo Clinic (P50 AG016574), Mount Sinai School of Medicine (P50 AG005138), New York University (P30 AG08051, UO1 AG16976, MO1 RR00096, and UL1 RR029893), Northwestern University (P30 AG013854), Oregon Health & Science University (P30 AG008017), Rush University (P30 AG010161), University of Alabama at Birmingham (P50 AG016582, UL1 RR02777 through the UAB Center for Clinical and Translational Science), University of California, Davis (P30 AG010129), University of California, Irvine (P50 AG016573, P50 AG016574, P50 AG016575, P50 AG016576, P50 AG016577), University of California, Los Angeles (P50 AG016570), University of California, San Diego (P50 AG005131), University of California, San Francisco (P50 AG023501, P01 AG019724), University of Kentucky (P30 AG028383), University of Michigan (P50 AG008671), University of Pennsylvania (P30 AG010124), University of Pittsburgh (P50 AG005133), University of Southern California (P50 AG005142), University of Texas Southwestern (P30 AG012300), University of Washington (P50 AG005136), and the Washington University (P50 AG005681 and P01 AG03991). The work completed by Boston University is also supported by the Alzheimer’s Association (IIRG-08-89720) and VA New England Geriatric Research Education and Clinical Center.

We thank Drs. Creighton Phelps, Ph.D., Marcelle Morrison-Bogorad, Ph.D., and Marilyn Miller Ph.D. from the National Institute on Aging for helping in acquiring samples and data and who are ex-officio members of the ADGC. Duke University would also like to acknowledge John Ervin from the Brain Bank and Kathleen Hayden in the Clinical Core for their respective efforts in the DNA/data pulls required. Dr. Rosenberg is Editor of Archives of Neurology and obtained an independent review and assessment of this paper from outside the editorial office prior to its acceptance.

This project was also made possible by the many contributions of individual study datasets, supported in part by NIH. These include NIA LOAD (NIH U24 AG026395), Columbia University study (NIH R37 AG015473), ADNI (U01 AG024904, RC2 AG036535), FHS (N01-HC-25195, R01-NS017950, R01-AG08122, R01-AG16495, R01-AG033193 and R01-AG031287), CAMP (R01 AG019085), JHU (R01 AG020688), MIRAGE (R01 AG009029), Wadi Ara (R01 AG017173), and the Multi-ethnic GWAS (Farrer - R01 AG025259). The UM/VU/MSS work was supported by grants from the NIA-NIH (AG010491, AG002219, AG005138, AG027944, AG021547, AG019757 and R01-AG-027944) and from the Alzheimer’s Association (IIRG-05-14147). A subset of these participants was ascertained while Dr. Margaret A. Pericak-Vance was a faculty member at Duke University. The study by Oregon Health & Science University was supported by the National Institute on Aging (grants R01 AG026916, P30 AG028377, P50 AG005146, P30 AG028383, P50 AG16574, U01 AG06786, P30 AG008017, P30 AG10161, R01 AG17917, P30 AG10129, P50 AG05131, P50 AG08671, P50 AG05681, P01 AG03991, U01 AG016976) of the National Institutes of Health, and by the Natural Science Foundation of China NSFC, project number 30730057 and 30700442. TGEN is supported by NIH grant R01 AG031581, Kronos Life Sciences and the state of Arizona.

ADNI data collection and sharing for this project was funded by the National Institutes of Health Grant U01 AG024904 (PI Michael W. Weiner). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., and Wyeth, as well as non-profit partners the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation, with participation from the U.S. Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health ( <> < > > ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation.

#. ADGC members

Steven E. Arnold, MD; Clinton T. Baldwin, PhD; Robert Barber, PhD; Thomas Beach, MD, PhD; Eileen H. Bigio, MD; Thomas D. Bird, MD; Adam Boxer, MD, PhD; James R. Burke, MD, PhD; Nigel Cairns, PhD FRCPath; Steven L. Carroll, MD, PhD; Helena C. Chui, MD; David G. Clark, MD; Carl W. Cotman, PhD; Jeffrey L. Cummings, MD; Charles DeCarli, MD; Ramon Diaz-Arrastia, MD, PhD; Malcolm Dick, PhD; Dennis W. Dickson, MD; William G. Ellis, MD; Kenneth B. Fallon, MD; Martin R. Farlow, MD; Steven Ferris, PhD; Matthew P. Frosch, MD, PhD; Douglas R. Galasko, MD; Marla Gearing, PhD; Daniel H. Geschwind, MD, PhD; Bernardino Ghetti, MD; Sid Gilman, MD FRCP; Bruno Giordani, PhD; Jonathan Glass, MD; Neill R. Graff-Radford, MD; Robert C. Green, MD; John H. Growdon, MD; Ronald L. Hamilton, MD; Lindy E. Harrell, MD, PhD; Elizabeth Head, PhD; Lawrence S. Honig, MD, PhD; Christine M. Hulette, MD; Bradley T. Hyman, MD, PhD; Gregory A. Jicha, MD, PhD; Lee-Way Jin, MD, PhD; Nancy Johnson, PhD; Jason Karlawish, MD; Anna Karydas, BA; Jeffrey A. Kaye, MD; Ronald Kim, MD; Edward H. Koo, MD; Neil W. Kowall, MD; James J. Lah, MD, PhD; Allan I. Levey, MD, PhD; Andrew Lieberman, MD, PhD; Oscar L. Lopez, MD; Wendy J. Mack, PhD; William Markesbery, MD; Daniel C. Marson, JD, PhD; Frank Martiniuk, PhD; Eliezer Masliah, MD; Ann C. McKee, MD; Marsel Mesulam, MD; Joshua W. Miller, PhD; Bruce L. Miller, MD; Carol A. Miller, MD; Joseph E. Parisi, MD; Daniel P. Perl, MD; Elaine Peskind, MD; Ronald C. Petersen, MD, PhD; Wayne Poon, PhD; Joseph F. Quinn, MD; Murray Raskind, MD; Barry Reisberg, MD; John M. Ringman, MD; Erik D. Roberson, MD, PhD; Roger N. Rosenberg, MD; Mary Sano, PhD; Julie A. Schneider, MD; Lon S. Schneider, MD; William Seeley, MD; Michael L. Shelanski, MD, PhD; Charles D. Smith, MD; Salvatore Spina, MD; Robert A. Stern, PhD; Rudolph E. Tanzi, PhD; John Q. Trojanowski, MD, PhD; Juan C. Troncoso, MD; Vivianna M. Van Deerlin, MD, PhD; Harry V. Vinters, MD; Jean Paul Vonsattel, MD; Sandra Weintraub, PhD; Kathleen A. Welsh-Bohmer, PhD; Randall L. Woltjer, MD, PhD; Steven G. Younkin, MD, PhD.

Author Affiliations

Departments of Medicine (Genetics Program) (Dr. Jun, Ms. Buros, and Drs. Farrer and Baldwin), Opthamology (Dr. Jun), Biostatistics (Drs. Jun, Lunetta and Cupples), Neurology (Drs. Farrer, Green, Kowall, McKee and Stern), Genetics & Genomics and Epidemiology (Drs. Farrer and Green), and Pathology (Drs. Kowall and McKee), Boston University, Massachusetts; The John P. Hussman Institute for Human Genomics (Drs. Naj and Beecham, Mr. Gallins, and Dr. Pericak-Vance), and Dr. John T. Macdonald Foundation Department of Human Genetics (Drs. Beecham, Martin and Pericak-Vance), University of Miami, Florida; Departments of Pathology and Laboratory Medicine (Dr. Wang, Ms. Cantwell, Drs. Dombroski, Schellenberg, Trojanowski, and Van Deerlin), Psychiatry (Dr. Arnold) and Medicine (Dr. Karlawish), University of Pennsylvania School of Medicine, Philadelphia; Departments of Psychiatry (Drs. Buxbaum, Perl and Sano), Neuroscience (Drs. Buxbaum and Perl), Genetics and Genomic Sciences (Dr. Buxbaum), and Pathology (Dr. Perl), Mount Sinai School of Medicine, New York, New York; Departments of Neuroscience (Drs. Ertekin-Taner and Dickson), Neurology (Drs. Ertekin-Taner and Graff-Radford), and Pharmacology (Dr. Younkin), Mayo Clinic Jacksonville, Florida; Departments of Epidemiology (Dr. Fallin) and Pathology (Dr. Troncoso), Johns Hopkins University, Baltimore, Maryland; Department of Neurology, University of Louisville, Kentucky (Dr. Friedland); Sheba Medical Center, Departments of Neurology and Medicine, Tel Aviv University, Israel (Dr. Inzelberg); Departments of Neurology (Drs. Kramer, Kaye and Quinn), Molecular & Medical Genetics (Dr. Kramer), Biomedical Engineering (Dr. Kaye), and Pathology (Dr. Woltjer), Oregon Health & Science University, Portland, Oregon; Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Ontario, Canada (Drs. Rogaeva and St George-Hyslop); Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (Dr. St George-Hyslop); Departments of Radiology and Imaging Sciences (Dr. Saykin), Medical and Molecular Genetics (Drs. Saykin, Foroud), Neurology (Dr. Farlow), and Pathology and Laboratory Medicine (Drs. Ghetti and Spina), Indiana University, Indianapolis; Arizona Alzheimer’s Consortium and Banner Alzheimer’s Institute and Neurogenomics Division, Translational Genomics Research Institute and Department of Psychiatry, University of Arizona, University of Arizona, Phoenix (Dr. Reiman); Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona (Dr. Beach); Rush Alzheimer’s Disease Center (Dr. Bennett) and Departments of Neurological Sciences (Drs. Bennett and Schneider) and Pathology (Dr. Schneider), Rush University Medical Center, Chicago, Illinois; Departments of Neurology (Dr. Morris), Pathology and Immunology (Drs. Morris and Cairns) and Psychiatry (Dr. Goate), Washington University, St. Louis, Missouri; Department of Pathology (Dr. Montine), Psychiatry and Behavioral Sciences (Drs. Tsuang, Peskind and Raskind), National Alzheimer’s Coordinating Center (Mr. Beekly and Dr. Kukull), Departments of Epidemiology (Dr. Kukull), Neurology (Dr. Bird), University of Washington, Seattle; Departments of Psychiatry and Epidemiology (Dr. Blacker), C.S. Kubik Laboratory for Neuropathology (Dr. Frosch), Departments of Neurology (Drs. Growdon, Hyman, and Tanzi), Massachusetts General Hospital, Charlestown, Massachusetts; Center for Applied Genomics, Children’s Hospital of Philadelphia, Pennsylvania (Dr. Hakonarson); Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee (Dr. Haines); Sergievsky Center (Dr. Mayeux), Taub Institute (Drs. Mayeux, Honig and Vonsattel), and Departments of Neurology (Dr. Honig), and Pathology (Dr. Shelanski), Columbia University, New York, New York; Departments of Pharmacology and Neuroscience (Dr. Barber) and Neurology (Drs. Diaz-Arrastia and Rosenberg), University of Texas Southwestern, Fort Worth, Texas; Departments of Pathology (Dr. Bigio), Psyhiatry and Behavioral Sciences (Dr. Johnson), and Cognitive Neurology and Alzheimer’s Disease Center (Drs. Mesulam and Weintraub), Northwestern University, Chicago, Illinois; Departments of Neurology University of California San Francisco (Dr. Boxer, Ms. Karydas, and Drs. Miller and Seeley); Departments of Neurology (Drs. Clark, Harrell, Marson and Roberson), and Pathology (Drs. Carroll, Fallon), University of Alabama at Birmingham; Departments of Medicine (Drs. Burke and Welsh-Bohmer), Pathology (Dr. Hulette), and Psychiatry & Behavioral Sciences (Dr. Welsh-Bohmer), Duke University, Durham, North Carolina; Departments of Neurology (Drs. Chui and Schneider), Preventive Medicine (Dr. Mack), Pathology (Dr. Miller), and Psychiatry (Dr. Schneider), University of Southern California, Los Angeles; Institute for Memory Impairments and Neurological Disorders (Drs. Cotman, Dick, and Poon), and Departments of Molecular and Biomedical Pharmacology (Dr. Head), and Pathology and Laboratory Medicine (Dr. Kim), University of California Irvine; Department of Neurology (Drs. Cummings, Ringman and Vinters), Neurogenetics Program (Dr. Geschwind), and Department of Pathology & Laboratory Medicine (Dr. Vinters), University of California Los Angeles; Departments of Neurology (Dr. DeCarli) and Pathology and Laboratory Medicine (Drs. Ellis, Jin and Miller), University of California Davis; Departments of Psychiatry (Drs. Ferris and Reisberg) and Medicine (Dr. Martiniuk), and Alzheimer’s Disease Center (Dr. Reisberg), New York University, New York; Departments of Neurosciences (Drs. Galasko, Koo and Masliah) and Pathology (Dr. Masliah), University of California San Diego; Department of Pathology and Laboratory Medicine and Emory Alzheimer’s Disease Center (Dr. Gearing), and Departments of Neurology (Drs. Glass, Lah and Levey), and Pathology (Dr. Glass), Emory University, Atlanta, Georgia; Departments of Neurology (Dr. Gilman), Psychiatry (Dr. Giordani), and Pathology (Dr. Lieberman), University of Michigan, Ann Arbor; Departments of Pathology (Neuropathology) (Dr. Hamilton) and Neurology (Dr. Lopez), University of Pittsburgh, Pennsylvania; Departments of Neurology (Drs. Jicha, Markesbery and Smith) and Pathology (Dr. Markesbery), University of Kentucky, Lexington; Departments of Anatomic Pathology, and Laboratory Medicine and Pathology (Dr. Parisi) and Neurology (Dr. Petersen) Mayo Clinic Rochester, New York.

Author Contributions

Study concept and design: Bennett, Blacker, Buxbaum, Ertekin-Taner, Farrer, Foroud, Goate, Haines, Hakonarson, Kramer, Kukull, Martin, Mayeux, Montine, Morris, Pericak-Vance, Reiman, Saykin, Schellenberg, and Tsuang. Acquisition of data: Arnold, Baldwin, Barber, Beach, Beekly, Bennett, Bigio, Bird, Boxer, Burke, Cairns, Cantwell, Carroll, Chui, Clark, Cotman, Cummings, DeCarli, Diaz-Arrastia, Dick, Dickson, Dombroski, Ellis, Fallin, Fallon, Farlow, Ferris, Foroud, Friedland, Frosch, Galasko, Gearing, Geschwind, Ghetti, Gilman, Giordani, Glass, Graff-Radford, Green, Growdon, Haines, Hakonarson, Hamilton, Harrell, Head, Honig, Hulette, Hyman, Inzelberg, Jicha, Jin, Johnson, Karlawish, Karydas, Kaye, Kim, Koo, Kowall, Lah, Levey, Lieberman, Lopez, Mack, Markesbery, Marson, Martiniuk, Masliah, Mayeux, McKee, Mesulam, Miller, Miller, Miller, Parisi, Perl, Peskind, Petersen, Poon, Quinn, Raskind, Reiman, Reisberg, Ringman, Roberson, Rogaeva, Rosenberg, Sano, Saykin, Schellenberg, Schneider, Schneider, Seeley, Shelanski, Smith, Spina, St George-Hyslop, Stern, Tanzi, Trojanowski, Troncoso, Van Deerlin, Vinters, Vonsattel, Weintraub, Welsh-Bohmer, Woltjer, and Younkin. Analysis and interpretation of data: Beecham, Buros, Cupples, Farrer, Gallins, Haines, Jun, Kramer, Kukull, Lunetta, Martin, Montine, Morris, Naj, Pericak-Vance, Schellenberg, Tsuang, and Wang. Drafting of the manuscript: Beecham, Bennett, Buros, Buxbaum, Ertekin-Taner, Farrer, Foroud, Gallins, Haines, Jun, Kramer, Mayeux, Morris, Naj, Pericak-Vance, Reiman, Saykin, Schellenberg, Wang. Critical revision of the manuscript for important intellectual content: Arnold, Baldwin, Barber, Beach, Beecham, Beekly, Bennett, Bigio, Bird, Blacker, Boxer, Burke, Buros, Buxbaum, Cairns, Cantwell, Carroll, Chui, Clark, Cotman, Cummings, Cupples, DeCarli, Diaz-Arrastia, Dick, Dickson, Dombroski, Ellis, Ertekin-Taner, Fallin, Fallon, Farlow, Farrer, Ferris, Foroud, Friedland, Frosch, Galasko, Gallins, Gearing, Geschwind, Ghetti, Gilman, Giordani, Glass, Goate, Graff-Radford, Green, Growdon, Haines, Hakonarson, Hamilton, Harrell, Head, Honig, Hulette, Hyman, Inzelberg, Jicha, Jin, Johnson, Jun, Karlawish, Karydas, Kaye, Kim, Koo, Kowall, Kramer, Kukull, Lah, Levey, Lieberman, Lopez, Lunetta, Mack, Markesbery, Marson, Martin, Martiniuk, Masliah, Mayeux, McKee, Mesulam, Miller, Miller, Miller, Montine, Morris, Naj, Parisi, Pericak-Vance, Perl, Peskind, Petersen, Poon, Quinn, Raskind, Reiman, Reisberg, Ringman, Roberson, Rogaeva, Rosenberg, Sano, Saykin*, Schellenberg, Schneider, , Schneider, Seeley, Shelanski, Smith, Spina, St George-Hyslop, Stern, Tanzi, Trojanowski, Troncoso, Tsuang, Van Deerlin, Vinters, Vonsattel, Wang, Weintraub, Welsh-Bohmer, Woltjer, and Younkin. Statistical analysis: Beecham, Buros, Cupples, Farrer, Gallins, Haines, Jun, Lunetta, Naj, Pericak-Vance, and Wang. Obtained funding: Bennett, Blacker, Farrer, Foroud, Goate, Haines, Hakonarson, Kukull, Mayeux, Montine, Morris, Pericak-Vance, Reiman, Saykin, Schellenberg, Tsuang, and Wang. Administrative, technical, and material support: Arnold, Baldwin, Barber, Beach, Beekly, Bigio, Bird, Boxer, Burke, Buros, Cairns, Cantwell, Carroll, Chui, Clark, Cotman, Cummings, DeCarli, Diaz-Arrastia, Dick, Dickson, Dombroski, Ellis, Fallin, Fallon, Farlow, Ferris, Friedland, Frosch, Galasko, Gallins, Gearing, Geschwind, Ghetti, Gilman, Giordani, Glass, Graff-Radford, Green, Growdon, Hakonarson, Hamilton, Harrell, Head, Honig, Hulette, Hyman, Inzelberg, Jicha, Jin, Johnson, Karlawish, Karydas, Kaye, Kim, Koo, Kowall, Kukull, Lah, Levey, Lieberman, Lopez, Mack, Markesbery, Marson, Martiniuk, Masliah, McKee, Mesulam, Miller, Miller, Miller, Parisi, Perl, Peskind, Petersen, Poon, Quinn, Raskind, Reisberg, Ringman, Roberson, Rogaeva, Rosenberg, Sano, Schellenberg, Schneider, Schneider, Seeley, Shelanski, Smith, Spina, Stern, St George-Hyslop, Tanzi, Trojanowski, Troncoso, Van Deerlin, Vinters, Vonsattel, Weintraub, Welsh-Bohmer, Woltjer, and Younkin. Study supervision: Beekly, Cantwell, Farrer, Kukull, Pericak-Vance, Schellenberg.


1. Goate A, Chartier-Harlin M-C, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349:704–706. [PubMed]
2. Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 1995;375:754–760. [PubMed]
3. Rogaev EI, Sherrington R, Rogaeva EA, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature. 1995;376:775–778. [PubMed]
4. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269:973–977. [PubMed]
5. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene Dose of Apolipoprotein-E Type-4 Allele and the Risk of Alzheimer’s Disease in Late Onset Families. Science. 1993;261:921–923. [PubMed]
6. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1088–U1061. [PMC free article] [PubMed]
7. Lambert JC, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1094–U1068. [PubMed]
8. Saykin A, Shen L, Foroud TM, Potkin SG, Swaminathan S, Kim S, Risacher SL, Nho K, Huentelman MJ, Craig DW, Thompson PM, Stein JL, Moore JH, Farrer LA, Green RC, Bertram L, Jack CR, Weiner MW. Alzheimer’s Disease Neuroimaging Initiative ADNI biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans. Alzheimer’s and Dementia. 2010;6:265–273. [PMC free article] [PubMed]
9. McCauley JL, Hahs DW, Jiang L, et al. Combinatorial Mismatch Scan (CMS) for loci associated with dementia in the Amish. BMC Med Genet. 2006;7:19. [PMC free article] [PubMed]
10. Hahs DW, McCauley JL, Crunk AE, et al. A genome-wide linkage analysis of dementia in the Amish. American Journal of Medical Genetics Part B Neuropsychiatric Genetics. 2006;141B(2):160–166. [PMC free article] [PubMed]
11. Lee JH, Barral S, Cheng R, et al. Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease. Neurogenetics Feb. 2008;9(1):51–60. [PMC free article] [PubMed]
12. Dawber TR, Kannel WB. The Framingham study. An epidemiological approach to coronary heart disease. Circulation. 1966 Oct;34(4):553–555. [PubMed]
13. Splansky GL, Corey D, Yang Q, et al. The Third Generation Cohort of the National Heart, Lung, and Blood Institute’s Framingham Heart Study: design, recruitment, and initial examination. Am J Epidemiol. 2007 Jun 1;165(11):1328–1335. [PubMed]
14. Cobb JL, Wolf PA, Au R, White R, D’Agostino RB. The effect of education on the incidence of dementia and Alzheimer’s disease in the Framingham Study. Neurology Sep. 1995;45(9):1707–1712. [PubMed]
15. Green RC, Cupples LA, Go R, et al. Risk of dementia among white and African American relatives of patients with Alzheimer disease. Jama - Journal of the American Medical Association. 2002 January 16;287(3):329–336. [PubMed]
16. Wijsman EMPN, Choi Y, Rothstein JH, Faber K, Cheng R, Lee JH, Bird T, Bennnett DA, Diaz-Arrastia R, Goate A, Farlow M, Sweet RA, Ghetti B, Foroud T, Mayeux R. for The NIA-LOAD/NCRAD Family Study Group. Genome wide association of familial late onset Alzheimer’s disease replicates BIN1, and nominates CUGBP2 in interaction with APOE. 2010 submitted. [PMC free article] [PubMed]
17. Coon KD, Myers AJ, Craig DW, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry. 2007;68:613–618. [PubMed]
18. Scott WK, Nance MA, Watts RL, et al. Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA. 2001;286:2239–2244. [PubMed]
19. Beecham GW, Martin ER, Li YJ, et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet Jan. 2009;84(1):35–43. [PubMed]
20. Edwards C. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson Annals of Human Genetics. 2010:2010. [PMC free article] [PubMed]
21. Naj. submitted. 2010
22. Haroutunian V, Perl DP, Purohit DP, et al. Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. Archives of Neurology. 1998 September;55(9):1185–1191. [PubMed]
23. Bowirrat A, Friedland RP, Chapman J, Korczyn AD. The very high prevalence of AD in an Arab population is not explained by APOE epsilon 4 allele frequency. Neurology. 2000;55(5):731. [PubMed]
24. Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD, Baldwin CT. Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community. Hum Molec Genet. 2003;12(4):415–422. [PubMed]
25. Inzelberg R, Schechtman E, Abuful A, et al. Education effects on cognitive function in a healthy aged Arab population. Int Psychogeriatr Jun. 2007;19(3):593–603. [PubMed]
26. IsraeliKorn SD, Masarwa M, Schechtman E, et al. Hypertension Increases the Probability of Alzheimer’s Disease and of Mild Cognitive Impairment in an Arab Community in Northern Israel. Neuroepidemiology. 34(2):99–105. [PMC free article] [PubMed]
27. Li M, Boehnke M, Abecasis GR. Efficient study designs for test of genetic association using sibship data and unrelated cases and controls. Am J Hum Genet. 2006;78:778–792. [PubMed]
28. Pritchard JK, Stephens M, Donnelly PJ. Inference of population structure using multilocus genotype data. Genetics. 2000;155:945–959. [PubMed]
29. Pritchard JK, Stephens M, Rosenberg NA, Donnelly P. Association mapping in structured populations. Am J Hum Genet. 2000;67:170–181. [PubMed]
30. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–909. [PubMed]
31. R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing V; Austria: 2009. URL
32. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002 Jun 15;21(11):1539–1558. [PubMed]
33. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003 Sep 6;327(7414):557–560. [PMC free article] [PubMed]
34. Petersen RC, Aisen PS, Beckett LA, et al. Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010 Jan 19;74(3):201–209. [PMC free article] [PubMed]
35. Kramer PL, Xu H, Woltjer RL, Westaway SK, Clark D, Erten-Lyons D, Kaye JA, Welsh-Bohmer KA, Troncoso JC, Markesbery WR, Petersen RC, Turner RS, Kukull WA, Bennett DA, Galasko D, Morris JC, Ott J. Alzheimer’s disease pathology in cognitively healthy elderly: A genome-wide study. Neurobiology of Aging. 2010:2010. (in press) [PMC free article] [PubMed]
36. Feinleib M, Kannel WB, Garrison RJ, McNamara PM, Castelli WP. The Framingham Offspring Study. Design and preliminary data. Prev Med. 1975 Dec;4(4):518–525. [PubMed]
37. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: A meta-analysis. JAMA. 1997;278:1349–1356. [PubMed]
38. Pastor P, Roe CM, Villegas A, et al. Apolipoprotein E epsilon 4 modifies Alzheimer’s disease onset in an E280A PS1 kindred. Ann Neurol. 2003;54:163–169. [PubMed]
39. Wijsman EM, Daw E, Yu X, et al. APOE and other loci affect age-at-onset in Alzheimer’s disease families with PS2 mutation. Am J Med Genet Neuropsych Genet. (in press) [PubMed]
40. St George-Hyslop P, Crapper McLachlan D, Tuda T, et al. Alzheimer’s disease and possible gene interaction. Science. 1994;263:537. [PubMed]
41. Seshadri S, Fitzpatrick AL, Ikram MA, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010 May 12;303(18):1832–1840. [PMC free article] [PubMed]
42. Price JL, McKeel DW, Buckles VD, et al. Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009;30(7):1026–1036. [PMC free article] [PubMed]
43. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18(4):351–357. [PubMed]
44. Bennett DA, Schneider JA, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology. 2006 Jun 27;66(12):1837–1844. [PubMed]
45. Hulette CM, Welshbohmer KA, Murray MG, Saunders AM, Mash DC, Mcintyre LM. Neuropathological and neuropsychological changes in “normal” aging: Evidence for preclinical Alzheimer disease in cognitively normal individuals. J Neuropathol Exp Neurol. 1998;57(12):1168–1174. [PubMed]
46. Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS. Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology. 2005;64(5):834–841. [PubMed]
47. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature. 2009;461(7266):916–922. [PMC free article] [PubMed]
48. Reiman EM, Webster JA, Myers AJ, et al. GAB2 alleles modify Alzheimer’s risk in APOE epsilon 4 carriers. Neuron. 2007;54(5):713–720. [PMC free article] [PubMed]
49. Carrasquillo MM, Zou F, Pankratz VS, et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nat Genet Feb. 2009;41(2):192–198. [PMC free article] [PubMed]
50. Poduslo SE, Huang R, Huang J, Smith S. Genome screen of late-onset Alzheimer’s extended pedigrees identifies TRPC4AP by haplotype analysis. Am J Med Genet B Neuropsychiatr Genet. 2009 Jan 5;150B(1):50–55. [PubMed]
51. Bertram L, Lange C, Mullin K, et al. Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet Nov. 2008;83(5):623–632. [PubMed]
52. Li H, Wetten S, Li L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Archives of Neurology. 2008;65(1):45–53. [PubMed]
53. Feulner TM, Laws SM, Friedrich P, et al. Examination of the current top candidate genes for AD in a genome-wide association study. Mol Psychiatry. 2009 Jan 6; [PubMed]