Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes
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OBJECTIVES: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. DESIGN: Association study of AD and CLU, PICALM, CR1, and APOE genotypes. SETTING: Academic research institutions in the United States, Canada, and Israel. PARTICIPANTS: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. RESULTS: 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; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE ε4, and an interaction term showed significant interaction between presence or absence of APOE ε4 and PICALM. CONCLUSIONS: We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.
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For clinical and combined groups, the analysis accounted for family structure due to containing families from the Multi-Institutional Research on Alzheimer's Genetic Epidemiology and NIA Late-onset AD (NIA-LOAD) study under a logistic regression using generalized estimating equations.
“For clinical and combined groups, we further accounted for family structure due to containing families from the Multi-Institutional Research on Alzheimer’s Genetic Epidemiology and NIA Late-onset AD (NIA-LOAD) study32 under a logistic regression using generalized estimating equations.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [32]
There is a reported genetic interaction between the PICALM risk-allele and APOE4.
“Given the reported genetic interaction between the PICALM risk-allele and APOE419,58, it will be interesting to empirically examine possible epistasis between these two AD risk factors.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [58]
Stage 1 discovery meta-analysis produced 12 loci with genome-wide significance (P ≤ 5 × 10−8), all previously described.
“The Stage 1 discovery meta-analysis produced 12 loci with genome-wide significance (P ≤ 5 × 10−8) (Table 1), all of which are previously described1,4–11.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [9]
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“…genetic support from genome-wide association studies that have identified several single nucleotide polymorphisms in immune-related genes that increase the risk of developing late onset AD (Lambert et al., 2009; Jun et al., 2010; Naj et al., 2011; Guerreiro et al., 2013; Jonsson et al., 2013).”
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“, 2016), while variants in the PICALM region exhibit stronger associations in APOE ε4+ subjects (Jun et al., 2010), further suggesting independent mechanisms may partially contribute to AD across APOE genotypes.”
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- Authors
- Jun, G.
- Affiliations
- Boston University (US)
- Corresponding author
- Jun, Gyungah
- ORCID
- Jun, Gyungah
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2010-12-01
- Volume
- 67
- Issue
- 12
- Pages
- 1473
- ISSN
- 0003-9942 (ISSN-L)
- PMC
- PMC3048805
- OpenAlex
- W2171610997
- Cited by
- 422
- References
- 55
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 14 · 2023: 14 · 2022: 14 · 2021: 25 · 2020: 24 · 2019: 20 · 2018: 31 · 2017: 26 · 2016: 27 · 2015: 31 · 2014: 43 · 2013: 37 · 2012: 45
- FWCI
- 28.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Foundation for the National Institutes of Health (P30AG010129, P50 AG16574, K01 AG030514, U01AG024904, AG024904, U01 AG016976)
- Alzheimer's Association (R01 AG17917, U01 AG016976, P30AG10161, AG010129, AG031287, AG08122, AG05681, U01 AG024904, NS017950, AG16495, AG033193, P50 AG005146, R01 AG019085)
- Dana Foundation (P30 AG010129, K01 AG030514, U01 AG024904)
- Massachusetts General Hospital
- University of Southern California (U01 AG024904)
- Vanderbilt University (R01 AG019085)
- University of Pennsylvania (U24 AG026395)
- Emory University
- Northwestern University
- University of Washington (P01 AG03991)
- Johns Hopkins University (P50-AG005146, AG020688, R01 AG020688, AG005146)
- University of Pittsburgh
- Northern California Institute for Research and Education (U01 AG024904, K01 AG030514, P30 AG010129)
- Wellcome Trust (081864)
- Translational Genomics Research Institute
- York University
- National Natural Science Foundation of China (U01 AG024904, 30730057)
- National Institutes of Health (AG028 383, 3u01ag024904-10s2, 5ul1rr025777-04, 5r01ag027944-05, n01hc25195-41-0-1, 7r01ag019757-06, 5r37ag015473-15, AG016976, U01-AG024904, AG005138, AG05681, P30 AG010129 and K01 AG030514, AG008017, AG010129, AG024904, AG05131, AG10129, AG10161, R37 AG015473, AG 03991, AG16574)
- University of California, Los Angeles
- University of California, Davis (P30AG010129, NS017950, AG033193, AG010129, AG16495, AG031287, AG08122)
- University of California, San Diego
- University of California, San Francisco
- University of California, Irvine
- National Institute on Aging (U01-AG-024904, AG 005138, R01AG017917, AG-028383, P01AG010491, P50 AG016575, AG 016976, P30AG010129, P30AG010133, R01AG019085, AG-16495, P50 AG016576, R01AG030146, AG021547, AG036535, AG03991, AG010491, R01AG037212, UO1 AG16976, AG05131, P30AG028383, P30AG012300, AG 025688, P50AG016577, AG-17917, AG008017, P50AG005133, R01-AG027944, AG 024904, P30AG028377, AG 16574, R01AG031287, U01AG016976, P50AG005131, R01-AG019757, R37-AG015473, P50AG005138, AG031287, P50AG016570, U01AG006786, K01AG030514, P30AG010124, P50AG016573, AG019757, R01AG021547, AG010129, AG 05681, U01AG010483, R01AG015819, P30AG008017, AG08122, P30AG010161, AG031581, AG019085, U01AG032984, AG028377, AG-10129, AG033193, NS017950, R01AG031581, P30AG008051, R01AG041797, P50AG016582, P50AG008702, R01AG016495, K24AG027841, P50AG005681, P50AG005142, R01AG032990, AG002219, P50AG008671, P30AG019610, R01AG026916, P50AG005146, P01AG003991, U24AG026395, P30AG013846, P50AG005136, P50AG005134, RC2AG036535, P30AG013854, U19AG010483, R01AG025259, P50AG025688, R01AG009029, R01AG017173, RC2AG036528, R01AG033193, P01AG002219, R01AG008122, U24AG056270, P01AG019724, U24AG021886, P50AG023501, AG027944, R01AG020688, P50AG016574)
- National Heart, Lung, and Blood Institute (N01‐HC25195, N01-HC-025195)
- National Institute of Mental Health (R01MH080295)
- National Human Genome Research Institute (R01HG002213, U01HG006375)
- National Cancer Institute (R01CA129769, U54CA137788, U54CA132378)
- National Institute of Neurological Disorders and Stroke (K08NS054811, R01NS017950)
- National Institute of Biomedical Imaging and Bioengineering (U01 AG024904, AG024904)
- National Center for Research Resources (MO1 RR000-96, UL1-RR-025777, UL1RR02777, UL1RR029893, M01RR000096)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, genetic susceptibility, complement receptor 1, clusterin, PICALM, APOE ε4, gene-gene interaction, genetic susceptibility loci, single nucleotide polymorphisms, ethnic differences, European ancestry populations
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Gene Frequency, Genotype, Humans, Male, Risk Factors, Meta-Analysis as Topic, Cohort Studies, Confidence Intervals, Odds Ratio, Receptors, Complement 3b, Polymorphism, Single Nucleotide, Monomeric Clathrin Assembly Proteins, White People, Clusterin, Genome-Wide Association Study
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