Non‐APOE variants predominately expressed in smooth muscle cells contribute to the influence of Alzheimer's disease genetic risk on white matter hyperintensities

Chandler, Hannah Louise, Wheeler, Joshua, Escott‐Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Murphy, Kevin ORCID: https://orcid.org/0000-0002-6516-313X and Lancaster, Thomas Matthew ORCID: https://orcid.org/0000-0003-1322-2449 2024. Non‐APOE variants predominately expressed in smooth muscle cells contribute to the influence of Alzheimer's disease genetic risk on white matter hyperintensities. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 10.1002/alz.14455

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Abstract

AbstractINTRODUCTIONWhite matter hyperintensity volumes (WMHVs) are disproportionally prevalent in individuals with Alzheimer's disease (AD), potentially reflecting neurovascular injury. We quantify the association between AD polygenic risk score (AD‐PRS) and WMHV, exploring single‐nucleotide polymorphisms (SNPs) that are proximal to genes overexpressed in cerebrovascular cell species.METHODSIn a UK‐Biobank sub‐sample (mean age = 64, range = 45–81 years), we associate WMHV with (1) AD‐PRS estimated via SNPs across the genome (minus apolipoprotein E [APOE] locus) and (2) AD‐PRS estimated with SNPs proximal to specific genes that are overexpressed in cerebrovascular cell species.RESULTSWe observed a positive association between non‐APOE‐AD‐PRS and WMHVs. We further demonstrate an association between WMHVs and AD‐PRS constructed with SNPs that are proximal to genes over‐represented in smooth muscles cells (SMCs; β = 0.135, PFWE < 0.01) and internally replicated (PDISCOVERY+REPLICATION < 0.01).DISCUSSIONCommon AD genetic risk could explain physiological processes underlying vascular pathology in AD. SMC function may offer a treatment target to prevent WMHV‐related AD pathophysiology prior to the onset of symptoms.Highlights Alzheimer's disease (AD) risk factors such as apolipoprotein E (APOE) ε4, link to increased white matter hyperintensity volume (WMHV). WMHVs indicate vascular risk and neurovascular injury in AD. The broader genetic link between AD risk and WMHV is not fully understood. We quantify AD polygenic risk score (PRS) associations with WMHV, excluding APOE. AD‐PRS in smooth muscle cells (SMCs) shows a significant association with increased WMHV.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Physics and Astronomy Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Start Date: 2024-12-31
Publisher:	Wiley
ISSN:	1552-5260
Date of First Compliant Deposit:	10 January 2025
Date of Acceptance:	12 November 2024
Last Modified:	10 Jan 2025 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/175183

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