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. 2025 Jun;21(6):e70245.
doi: 10.1002/alz.70245.

Impact of APOE4-related dementia risk in underrepresented groups from the All of Us research program

Valentina Ghisays  1 , Ehsan Khajouei  2 , Ignazio S Piras  3 , Michael H Malek-Ahmadi  1 , Hillary D Protas  1 , Dhruman D Goradia  1 , Yinghua Chen  1 , Marcus Naymik  3 , Donald Saner  1 , Olivia J Veatch  4 , Clayton O Mansel  4 , Yi Su  1 , Matthew J Huentelman  3 , Jason H Karnes  2 , Eric M Reiman  1   3
Affiliations

Impact of APOE4-related dementia risk in underrepresented groups from the All of Us research program

Valentina Ghisays et al. Alzheimers Dement. 2025 Jun.

Abstract

Introduction: Longitudinal electronic health records (EHRs), "dementia" diagnostic codes, and genetic data from All of Us were used to see if there is a higher risk of dementia and an attenuated impact of apolipoprotein ε4 (APOE4) on Alzheimer's disease (AD) risk in Black and Hispanic/Latino groups.

Methods: Participants included 9,784 Hispanic/Latinos, 14,937 Non-Hispanic Blacks (NHB), and 60,388 Non-Hispanic Whites (NHWs) ≥age 60 without an initial dementia diagnosis.

Results: There was a significantly higher risk of developing a dementia diagnosis in Hispanic/Latino and NHB participants than NHW participants and comparably increased dementia hazard ratios in the Hispanic/Latino, NHB, and NHW APOE4 carriers than non-carriers (hazard ratio [HR] [95% confidence interval {CI}] 1.54 [1.25-1.91], 1.25 [1.00-1.57], and 1.55 [1.40-1.72]).

Discussion: Compared to NHW individuals, Hispanic/Latino and NHB individuals are at higher risk of developing a "dementia diagnosis" and comparably higher risk in APOE4 carriers than non-carriers. Plasma AD biomarkers could clarify the proportion of dementia cases with and without AD and the impact of APOE4 on AD in these groups.

Highlights: Hispanic/Latino and non-Hispanic Black individuals have a higher risk of all-cause dementia. The impact of apolipoprotein ε4 (APOE4) on dementia risk was similar in the studied ethnoracial groups. Plasma biomarkers could inform the risk of Alzheimer's disease (AD) and impact of APOE4 in these groups.

Keywords: APOE genotype; Alzheimer's disease; electronic health records; social determinants of health underrepresented groups.

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Conflict of interest statement

V.G., E.K., I.S.P., M.H.M‐A., H.D.P., D.D.G., Y.C., M.N., D.S., O.J.V., C.O.M., Y.S., M.J.H., and J.H.K., report no disclosures. E.M.R is a principal investigator of the NIH‐supported University of Arizona‐Banner Health All of Us Research Program, other studies that are supported by NIH, state of Arizona, and philanthropic grants, and prevention trials that receive NIH, industry (Lilly and Roche), and/or philanthropic support. He is a co‐founder, advisor and shareholder in ALZpath, a company that involved in the development and use of Alzheimer's disease biomarkers, including plasma pTau217, and an inventor of several patents that are not related to this study. He is a compensated advisor to Alzheon, Denali, Cognition Therapeutics, Enigma, Retromer Therapeutics, and Vaxxinity.

Figures

FIGURE 1
FIGURE 1
Survival curves for APOE4 allele copy in All of Us participants across ethnoracial groups. Kaplan‐Meier survival curves for APOE4 non‐carriers (APOE4 NC, red), heterozygotes (APOE4 HT, Blue), and homozygotes (APOE4 HM, green) in All of Us participants from three ethnoracial groups: (A) non‐Hispanic Black, (B) Hispanic/Latino, and (C) non‐Hispanic White. Additionally, survival curves are shown for (D) the overall cohort and (E) all APOE4 carriers combined (blue). APOE4, apolipoprotein ε4; HM, homozygote; HT, heterozygote.
FIGURE 2
FIGURE 2
Dementia hazard ratios relative to non‐Hispanic White reference group in the overall cohort. Cox proportional hazard ratio with 95% confidence intervals (CIs) in Hispanic/Latino and non‐Hispanic Black compared with the non‐Hispanic White reference group (1.00 ref.) from the overall cohort.
FIGURE 3
FIGURE 3
Distribution of deprivation index by ethnoracial group in the overall cohort. Percentages for low, medium, and high deprivation index tertiles in non‐Hispanic White, non‐Hispanic Black, and Hispanic/Latino groups from the overall cohort.
See this image and copyright information in PMC

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