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Genetic correlation analysis of Alzheimer's disease and stroke implicates PHLPP1 as a shared locus in individuals of African ancestry

Lookup NU author(s): Professor Raj KalariaORCiD

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Abstract

© 2026 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. INTRODUCTION: Neuropathological studies indicate a strong association between Alzheimer's disease (AD) and stroke, yet the molecular mechanisms underlying this association remain unclear. METHODS: Local genetic correlation analysis was conducted with LAVA (Local Analysis of [co]Variant Annotation) using the results from genome-wide association studies on AD and stroke in individuals of African ancestry. Enhanced Hi-C Capture Analysis (eHiCA) examined chromatin interactions using induced pluripotent stem cell (iPSC) -derived cells from AD brain autopsy samples. RESULTS: LAVA identified a region shared between AD and stroke on chromosome 18q21.33(rg = 0.77, p = 2.41×10-6). eHiCA demonstrated that the AD and stroke loci interact with regulatory elements in PHLPP1. Variants at PHLPP1 were also associated with AD in an independent set of individuals of African ancestry (p = 4.56 × 10-5). DISCUSSION: This study identified a region on top of PHLPP1 as a locus associated with both AD and stroke. PHLPP1 inhibits protein kinase B, which contributes to both AD and stroke pathophysiology.

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Author(s): Ray NR, Kurup J, Kumar A, Rajabli F, Wang L, Xu W, Jin F, Yilmaz E, Kizil C, Bertholim-Nasciben L, Moura S, Ramirez AM, 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, Blanton SH, Akpalu A, Cuccaro ML, Wahab K, McInerney KF, Nuytemans K, Obiako R, Mena PR, Okubadejo N, Martinez IM, Zewde YZ, Gugssa SA, Sarfo FS, Kalaria R, Ndetei DM, Williams SM, Caban-Holt A, Tosto G, Haines JL, Akinyemi RO, Ogunniyi A, Byrd GS, Bush WS, Kunkle BW, Vance JM, Pericak-Vance MA, Reitz C

Publication type: Article

Publication status: Published

Journal: Alzheimer's & Dementia

Year: 2026

Volume: 22

Issue: 4

Online publication date: 27/04/2026

Acceptance date: 27/02/2026

Date deposited: 11/05/2026

ISSN (print): 1552-5260

ISSN (electronic): 1552-5279

Publisher: Wiley

URL: https://doi.org/10.1002/alz.71433

DOI: 10.1002/alz.71433

PubMed id: 42043782

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