Abstract
INTRODUCTION
Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer’s disease (AD), but genetic drivers are unclear.
METHODS
In 2614 older adults (mean age ± SD: 73.7 ± 9.8 years; 26% cognitively impaired) from seven harmonized cohorts enriched for cognitive impairment, we quantified free-water–corrected diffusion MRI (dMRI) metrics in seven limbic tracts. We estimated single nucleotide polymorphism (SNP) heritability, performed cohort genome-wide association studies (GWASs) with meta-analysis, evaluated shared genetic architecture and enriched pathways, and assessed AD relevance using brain RNA-seq data.
RESULTS
Limbic WM is heritable (h2
= 0.26–0.60; pFDR
< 0.05). Meta-GWAS identified six loci (p < 5 × 10−
8), including a signal implicating CDH19, an oligodendrocyte-enriched cell-adhesion gene. Additional loci were near the KC6, SENP5, RORA, FAM107B, and MIR548A1 genes. In brain tissue, RORA, FAM107B, and KC6 expression was associated with cognition and AD neuropathology. Results converged on insulin and immune biology and shared genetic architecture with lipid and cardiovascular traits.
DISCUSSION
Limbic WM microstructure is genetically influenced and links oligodendrocyte and vascular-inflammatory biology to AD-relevant outcomes.
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This post is Copyright: | July 7, 2026
Neuro-Dementia