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

Alzheimers Dement. 2026 Apr;22(4):e71433. doi: 10.1002/alz.71433.

ABSTRACT

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(r_g = 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.

PMID:42043782 | DOI:10.1002/alz.71433