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Lookup NU author(s): Professor Raj KalariaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. BACKGROUND: Neuropathological and neuroimaging studies indicate that cerebrovascular disease (CVD) is a major risk factor for Alzheimer's disease (AD), yet the molecular mechanisms underlying the association between the two traits remain unclear. To elucidate the mechanistic relationship between the two phenotypes, the current study examined the genetic correlation between stroke and AD in individuals of African ancestry. METHOD: Capitalizing on the results from recent genome-wide association studies (GWAS) on AD (2,844 cases; 6,521 controls) and stroke (3,961 cases; 20,030 controls) in individuals of African ancestry, genetic correlation analysis was conducted using LAVA, which partitions the genome based on LD structure and estimates local genetic covariance within each resulting partition. Enhanced Hi-C Capture Analysis (eHiCA) was performed at identified top loci to examine chromatin interactions using 8 AD brain autopsy samples from different ancestries and iPSC-derived cells. In addition, overlapping top loci were examined in 553 African individuals with WGS data from the READD-ADSP. RESULT: Genetic covariance analysis identified a locus shared between AD and stroke on chromosome 18q21.33 that includes the PHLPP1 gene (ρ = .77, p = 2.41×10-6). Examination of the LD structure and genetic association patterns at this locus identified disease-associated haplotypes exerting an effect in the same direction in both traits. eHiCA demonstrated that the two haplotypes at PHLPP1 interact with each other, and both haplotypes interact with the same chromosome regions at and around PHLPP1. A similar pattern of chromatin interactions, which indicates a coordinated regulation of the same set of genes, was observed in brains across ancestries, and in different AD-relevant cell types (neurons, microglia, and oligodendrocytes). Variants at PHLPP1 were also nominally significant in the independent meta-analysis of African individuals that included WGS data (p = 4.56 × 10-5). CONCLUSION: These findings nominate PHLPP1 as a shared locus for both AD and stroke in individuals of African ancestry. Notably, a genome-wide significant signal in this locus was identified in an admixture mapping study of African Americans (Rajabli et al., 2023). Identification of shared molecular mechanisms between AD and CVD in different populations is useful for understanding the relationship between these two processes in all people.
Author(s): Ray NR, Kumar A, Kunkle BW, Rajabli F, Bush WS, Wang L, Xu W, Jin F, Yilmaz E, Kizil C, Nasciben LB, Moura S, Ramirez AM, Akinyemi RO, Ogunniyi A, Baiyewu O, Griswold AJ, Coker M, Scott KM, Akinwande K, Adams LD, Diala S, Whitehead PG, McCauley JL, Ogunronbi M, Hamilton-Nelson KL, Damasceno A, Zaman AF, Ndetei D, Blanton SH, Akpalu A, Cuccaro ML, Wahab K, McInerney KF, Nuytemans K, Obiako R, Mena PR, Okubadejo NU, Martinez IM, Kalaria R, Haines JL, Tosto G, Williams SM, Caban-Holt AM, Byrd GS, Vance JM, Pericak-Vance M, Reitz C
Publication type: Article
Publication status: Published
Journal: Alzheimer's & Dementia
Year: 2025
Volume: 21
Issue: S1
Online publication date: 25/12/2025
Acceptance date: 02/04/2018
Date deposited: 06/01/2026
ISSN (print): 1552-5260
ISSN (electronic): 1552-5279
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1002/alz70855_107411
DOI: 10.1002/alz70855_107411
PubMed id: 41447296
Notes: Supplement: Basic Science and Pathogenesis
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