Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database
Abstract
The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.
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The main genetic risk factor in sporadic Alzheimer's disease is the APOE gene.
“the main genetic risk factor in SAD is the APOE gene [91,92,93,94].”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [91]
BIN1 is the second most statistically significant AD susceptibility gene/locus based on a meta-analysis.
“Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer’s disease (AD).”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [25]
Fifty-two sex-specific KNDs of AD were also known AD genetic risk factors based on the AlzGene database and the genes identified from a large-scale meta-analysis carried out by the International Genomics of Alzheimer's Project (IGAP).
“Fifty-two sex-specific KNDs of AD were also known AD genetic risk factors based on the AlzGene database and the genes identified from a large-scale meta-analysis carried out by the International Genomics of Alzheimer’s Project (IGAP)”
From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [46]
CLU (apolipoprotein J) was identified as an AD risk gene by a large-scale meta-analysis.
“CLU also known as apolipoprotein J (APOJ), was identified as an AD risk gene by a large scale meta-analysis [46].”
From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [46]
APOE remains the most significant genetic risk factor for Alzheimer's disease across populations.
“Among the AD susceptibility genes/loci identified to date, APOE remains the most significant genetic risk factor across populations.”
From Association of rare <i>APOE</i> missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [9]
There is a strong positive correlation between the APOE ε4 allele and Aβ pathology in human AD brains, with the highest Aβ burden in homozygous APOE ε4 carriers.
“there is a strong positive correlation between the APOE ε4 allele and Aβ pathology in human AD brains with the highest Aβ burden found in homozygous APOE ε4 carriers”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bertram et al 2007
Numerous studies have confirmed that possession of the ε4 allele is the strongest genetic risk factor for both AD and CAA, or a combination of both disorders.
“Since then, numerous studies have confirmed that possession of the ε4 allele is the strongest genetic risk factor for both AD and CAA, or a combination of both disorders (Bertram et al., 2007; Farrer et al., 1997).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Bertram et al., 2007
BIN1 is the most important genetic risk factor in LOAD after APOE.
“Bridging integrator 1 (BIN1) has been identified as the most important genetic risk factor in LOAD after APOE [475].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [475]
In the most common form of AD, sporadic late-onset AD, many genetic variations contribute to increase or lower risk; greater than 20 have been identified.
“In the most common form of AD, sporadic late-onset AD, many genetic variations contribute to increase or lower risk; greater than 20 have been identified (AlzGene Database; www.alzgene.org).22”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [22]
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- Authors
- Bertram, L., McQueen, M. B., Mullin, K., Blacker, D., & Tanzi, R. E.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Bertram, Lars
- Venue
- Nature Genetics
- Published
- 2007-01
- Volume
- 39
- Issue
- 1
- Pages
- 17-23
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2017079501
- Cited by
- 1,857
- References
- 30
- Citations by year
- 2026: 22 · 2025: 36 · 2024: 71 · 2023: 56 · 2022: 57 · 2021: 60 · 2020: 83 · 2019: 91 · 2018: 109 · 2017: 82 · 2016: 99 · 2015: 82 · 2014: 134 · 2013: 135 · 2012: 144
- FWCI
- 62.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060726)
- 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 association studies, susceptibility genes, APOE ε4, polymorphism, case-control study, odds ratio, ACE, CHRNB2, presenilin 1, MTHFR, TFAM, TF
- MeSH terms
- Alzheimer Disease, Humans, Genetic Linkage, Polymorphism, Genetic, Genetic Heterogeneity, Genetic Predisposition to Disease, Databases, Genetic, Apolipoprotein E4
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