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Cited by 93Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles

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Bennett, David A., De Jager, Philip L., Leurgans, Sue E., Schneider, Julie A.·2009·Neurology
DOI 10.1212/wnl.0b013e3181a2e87dPMC PMC2677477
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Abstract

OBJECTIVE: The identification of susceptibility alleles to risk of Alzheimer disease (AD) is a major public health priority. Using apolipoprotein E genotype (APOE), we examined whether neuropathologic intermediate phenotypes, the pathology underlying clinical AD that presumably lies intermediate in the causal chain, would increase power for genetic associations. METHODS: More than 700 older persons underwent annual evaluation and organ donation as part of the Religious Orders Study or Rush Memory and Aging Project. A total of 536 autopsied persons with clinical AD or without dementia with APOE genotyping and a quantitative measure of AD pathology were analyzed. Regression analyses were used to examine the relation of APOE to clinical AD, to the level of cognitive function proximate to death, and to measures of AD neuropathology. RESULTS: APOE epsilon4 was associated with increased odds of clinical AD (p = 3 x 10(-7)), and its association with level of cognition was stronger (p = 8 x 10(-12)). However, the use of quantitative measures of AD pathology markedly enhanced the association (p = 9 x 10(-24)). The APOE epsilon2 was not associated with either AD (p = 0.69) or level of cognition (p = 0.82). However, its association with AD pathology (p = 1 x 10(-5)) was sufficiently strong that it would have warranted follow-up if discovered in a genome-wide association study. Power calculations demonstrate that a sample size of 625 subjects with our measure of AD pathology would be required to meet genome-wide significance of p = 5 x 10(-8) for epsilon2. CONCLUSION: Discovery efforts for susceptibility loci for Alzheimer disease could benefit from the use of neuropathologic intermediate phenotypes as a complement to other approaches.

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  • The APOE4 variant is the major genetic risk factor for Alzheimer's disease at the population level.

    “The APOE4 variant of apolipoprotein E was identified 30 years ago as the major genetic risk factor for Alzheimer’s Disease (AD) at the population level (Bennett et al, 2009; Corder et al, 1993; Strittmatter et al, 1993)”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Bennett et al, 2009

    The ‘Relation of APOE to clinical AD’ section reports that APOE ε4 was associated with more than threefold higher odds of clinical AD, and the Discussion calls APOE a well-established risk factor in multiple populations. Our copy does not establish that ε4 is the major genetic risk factor at the population level or document its identification 30 years ago. Page numbers were not provided for these passages. (LLM, conf=0.82)

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Authors
Bennett, D. A., De Jager, P. L., Leurgans, S. E., & Schneider, J. A.
Affiliations
  • Broad Institute (US)
  • From Rush Alzheimer's Disease Center and the Department of Neurological Sciences (D.A.B., S.E.L., J.A.S.) and Department of Pathology (Neuropathology) (J.A.S.), Rush University Medical Center, Chicago, IL; Center for Neurologic Diseases (P.L.D.), Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston; Partners Center for Personalized Genetic Medicine Boston (P.L.D.); and Program in Medical & Population Genetics (P.L.D.), Broad Institute of Harvard University...
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2009-04-28
Volume
72
Issue
17
Pages
1495-1503
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0b013e3181a2e87d
PMC
PMC2677477
OpenAlex
W2057329207
Cited by
93
References
8
Citations by year
2026: 1 · 2025: 1 · 2024: 6 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 1 · 2017: 6 · 2016: 6 · 2015: 7 · 2014: 6 · 2013: 14 · 2012: 8
FWCI
5.67
Type
journal article
Language
en
Open access
Locations
  • Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R01AG017917, R01AG015819, P30AG010161)
  • National Institute of Neurological Disorders and Stroke (K08NS046341)
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, APOE ε4, APOE ε2, APOE genotype, Alzheimer disease pathology, genetic susceptibility, cognitive function, statistical power, genome-wide association study, Religious Orders Study, Rush Memory and Aging Project
MeSH terms
Aged, Alzheimer Disease, Apolipoproteins E, Brain, Cognition Disorders, DNA Mutational Analysis, Female, Gene Frequency, Genetic Testing, Genotype, Humans, Male, Molecular Biology, Neuropsychological Tests, Phenotype, Polymorphism, Genetic, Predictive Value of Tests, Genetic Variation, Cohort Studies, Disease Progression, Genetic Predisposition to Disease, Apolipoprotein E4

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