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Basic Science and Pathogenesis.

Shea J Andrews1, Meri Okorie1, Ana I Boeriu1

  • 1University of California, San Francisco, San Francisco, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
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Summary
This summary is machine-generated.

Genomic-informed dementia risk reports improve Alzheimer's disease risk prediction across diverse populations. Tailored genetic and clinical risk scores enhance personalized prevention strategies for equitable dementia care.

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Area of Science:

  • Genetics and Genomics
  • Neuroscience
  • Epidemiology

Background:

  • Genomic-informed dementia risk reports (GIDRR) can improve Alzheimer's disease (AD) risk prediction and prevention.
  • Current AD risk models often lack validation in diverse populations, being primarily derived from non-Latinx White (NLW) individuals.
  • This study evaluates AD clinical and polygenic risk scores (CRS & PRS) in diverse groups, examining their combined impact with family history (FHx) and APOE on dementia risk.

Purpose of the Study:

  • To assess the predictive accuracy of AD clinical risk scores (CRS) and polygenic risk scores (PRS) in diverse populations.
  • To examine the combined effect of CRS, PRS, family history (FHx), and APOE on incident dementia.
  • To develop and validate genomic-informed dementia risk reports (GIDRR) for personalized prevention strategies.

Main Methods:

  • Constructed three AD-PRS models (single-ancestry, multi-ancestry, cross-ancestry) excluding APOE in the ADSP cohort (N=18,623) with diverse genetic ancestry groups.
  • Assessed AD-PRS associations with AD using logistic regression, adjusting for covariates.
  • Developed and evaluated two CRS (CAIDE and mCAIDE) in NACC & ADNI cohorts (N=20,755) comprising diverse reported populations, assessing associations with MCI/AD.
  • Constructed a GIDRR integrating mCAIDE, FHx, APOE*ε4, and high AD-PRS-CSx, and used Cox-proportional hazard models to estimate dementia progression risk.

Main Results:

  • AD-PRS models showed predictive value in 1KG-EUR-like, 1KG-AFR-like, and 1KG-AMR-like populations, particularly multi-ancestry and cross-ancestry PRS.
  • CAIDE scores predicted MCI/AD in Asian, Latinx, and NLW participants, while mCAIDE scores showed significant associations across all groups, strongest in Asians.
  • GIDRR demonstrated a dose-dependent increase in AD risk: one indicator (27% increase), two (83%), three (doubled risk), and four (fivefold increase).

Conclusions:

  • AD PRS and CRS models incorporating genetic ancestry and race/ethnicity show improved transportability and predictive accuracy.
  • Genomic-informed risk reports can facilitate equitable and personalized dementia prevention.
  • The findings support the development of inclusive risk prediction tools for Alzheimer's disease.