In 2,614 older adults (mean age 73.7 ± 9.8 years; 26% cognitively impaired) from seven harmonized aging cohorts, this cross-sectional imaging-genetics study estimated SNP heritability and performed meta-GWAS for free-water–corrected diffusion MRI metrics across seven limbic white matter tracts (cingulum, fornix, ILF, UF, and ITG/MTG/STG transcallosal tracts), then linked top loci to brain gene expression, cognition, and AD neuropathology via bulk RNA-seq.
Limbic WM microstructure was substantially heritable (h² = 0.26–0.60; pFDR < 0.05 for 15 of 35 metrics). Meta-GWAS identified six genome-wide significant loci (p < 5 × 10⁻⁸) near **CDH19** (oligodendrocyte-enriched cell-adhesion gene; 38 SNPs, lead rs12959877, p = 5.78 × 10⁻⁹), **KC6**, **SENP5**, **RORA**, **FAM107B**, and **MIR548A1**. Brain RNA-seq showed that higher *RORA* and *FAM107B* expression correlated with worse cross-sectional and longitudinal cognition and greater tau, neuritic plaque, neurofibrillary tangle, and Aβ burden; *KC6* expression in caudate nucleus associated with neuritic plaques. Genetic covariance analyses revealed shared architecture with HDL cholesterol, triglycerides, type 2 diabetes, heart rate variability, and multiple inflammatory diseases.
- Sample restricted to self-reported non-Hispanic White individuals, limiting generalizability to diverse populations. - Single-shell dMRI acquisitions constrain free-water bi-tensor model estimation; FW-corrected metrics remain nonspecific tissue-compartment measures rather than direct histopathologic markers. - Cross-sectional design precludes causal inference; WM hyperintensity burden and structural MRI volumes were not covaried, leaving residual cerebrovascular confounding possible.
Limbic white matter integrity in older adults has a meaningful genetic basis tied to oligodendrocyte, vascular, and inflammatory biology — not just AD-specific pathways. Clinicians should consider that vascular risk factors (dyslipidemia, type 2 diabetes, inflammation) may drive white matter degeneration that independently contributes to cognitive decline in aging and AD.
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