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Cited by 35Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

A novel age-informed approach for genetic association analysis in Alzheimer’s disease

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for the Alzheimer’s Disease Neuroimaging Initiative, Le Guen, Yann, Belloy, Michael E., Napolioni, Valerio, Eger, Sarah J., Kennedy, Gabriel, Tao, Ran, He, Zihuai +1 more·2021·Alzheimer's Research & Therapy
DOI 10.1186/s13195-021-00808-5PMC PMC8017764

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Abstract

Background: Many Alzheimer’s disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery. Methods: Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases). Results: Modeling variable AD risk across age results in 5–10% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3 , and TAOK2 genes. Conclusion: Our AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.

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  • MVP analyses were adjusted for sex, 3 principal components accounting for population stratification, and age at last examination.

    “These analyses were adjusted for sex, 3 principal components accounting for population stratification, and age at last examination, since the MVP is a population-based data set.20”

    From Association of African Ancestry–Specific <i>APOE</i> Missense Variant R145C With Risk of Alzheimer Disease (2023) · cites this paper as [20]

    The Methods section ('Statistics, association models, and AD-age score'; page unavailable) reports adjustment for sex and population-structure principal components, but specifies 10 components, not 3. The Methods ('Participants'; page unavailable) mentions age at last examination as a possible age measure for controls, not as an adjustment variable. These passages do not establish the stated adjustments for the MVP analyses. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Case-control analyses were not adjusted for age because controls were older than cases in some APOE ε3 genotype strata, and correcting for age when cases are younger than controls leads the model to incorrectly infer the age effect on AD risk, resulting in statistical power loss.

    “Case-control analyses were not adjusted for age given that controls were older than cases in some APOE ε3 genotype strata (Table 2).Correcting for age when cases are younger than controls leads the model to incorrectly infer the age effect on AD risk, resulting in statistical power loss.20”

    From Association of African Ancestry–Specific <i>APOE</i> Missense Variant R145C With Risk of Alzheimer Disease (2023) · cites this paper as [20]

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Cited by

Sorted by citations

Authors
Initiative, F. T. A. D. N., Le Guen, Y., Belloy, M. E., Napolioni, V., Eger, S. J., Kennedy, G., Tao, R., He, Z., & Greicius, M. D.
Affiliations
  • Università di Camerino (IT)
  • Stanford University (US)
  • Vanderbilt University (US)
  • Stanford Medicine (US)
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-04-01
Volume
13
Issue
1
Pages
72-72
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-021-00808-5
PMC
PMC8017764
OpenAlex
W3149537993
Cited by
35
References
8
Citations by year
2026: 4 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 4
FWCI
3.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Unicam Scientific Publications (University of Camerino) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (AG066206, AG060747, AG047366)
  • Alzheimer's Association (AARF-20-683984)
  • H2020 Marie Skłodowska-Curie Actions (890650)
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, age adjustment, statistical power, age of onset, exome-wide association, genotype imputation, KIF21B, USH2A, Rab10, RIN3, TAOK2, novel genetic variants
MeSH terms
Alzheimer Disease, Genetic Testing, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Association Studies, Exome

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