Faculty, Staff and Student Publications

Publication Date

4-1-2025

Journal

Alzheimer's & Dementia

DOI

10.1002/alz.70130

PMID

40219815

PMCID

PMC11992597

PubMedCentral® Posted Date

4-12-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Introduction: White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences.

Methods: To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores (PGSs) and WM metrics, and interactions with cognitive status.

Results: AD PGSs, variants in TMEM106B, PTK2B, WNT3, and apolipoprotein E (APOE), and interactions involving MS4A6A were significantly linked to WM microstructure.

Discussion: These findings implicate AD-related genetic factors related to neurodevelopment (WNT3), lipid metabolism (APOE), and inflammation (TMEM106B, PTK2B, MS4A6A) that contribute to alternations in WM microstructure in older adults.

Highlights: AD risk variants in TMEM106B, PTK2B, WNT3, and APOE genes showed distinct associations with limbic FW-corrected WM microstructure metrics. Interaction effects were observed between MS4A6A variants and cognitive status. PGS for AD was associated with higher FW content in the limbic system.

Keywords

Humans, White Matter, Alzheimer Disease, Female, Male, Aged, Middle Aged, Aged, 80 and over, Limbic System, Apolipoproteins E, Cohort Studies, Diffusion Tensor Imaging, Genetic Predisposition to Disease, Risk Factors, Alzheimer's disease, diffusion MRI, free water, genetic risk variants, polygenic risk, white matter microstructure

Published Open-Access

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