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. 2026 Mar;26(3):e70450.
doi: 10.1111/ggi.70450.

Glucose-Related Genetic Risk Score and Its Association With Cerebrovascular Abnormality, White-Matter Hyperintensity Volume, and Brain Microstructure Markers

Cheng-Chieh Lin  1   2   3 , Chia-Ing Li  1   2 , Chiu-Shong Liu  1   2   3 , Chih-Hsueh Lin  1   3 , Shing-Yu Yang  4 , Tsai-Chung Li  4   5
Affiliations

Glucose-Related Genetic Risk Score and Its Association With Cerebrovascular Abnormality, White-Matter Hyperintensity Volume, and Brain Microstructure Markers

Cheng-Chieh Lin et al. Geriatr Gerontol Int. 2026 Mar.

Abstract

Aim: Cerebral white-matter lesions serve as biomarkers for stroke, cardiovascular disease, and mortality. However, no genetic association studies on white-matter hyperintensities (WMH) have focused specifically on the Han Chinese population. Despite previous studies on candidate genes, none have explored association with glucose regulation. This study aimed to investigate the association between a genetic risk score (GRS) derived from glucose-related loci and cerebrovascular abnormality, cerebral WMH, and brain microstructure markers.

Methods: This study is a community-based family research conducted on 345 participants aged 65 years and over who provided brain magnetic resonance imaging (MRI) examinations and genome-wide association studies data. The volume of white-matter lesions was measured using brain MRI. Generalized linear models with generalized estimating equations were used to analyze the associations between GRSs and brain MRI parameters.

Results: Based on the 194 glucose-associated single-nucleotide polymorphisms (SNPs), the GRSs for cerebrovascular abnormality, WMH volume, and fractional anisotropy (FA) and mean diffusivity (MD) for four brain regions, namely, the right and left corticospinal tracts and the cingulate gyri, were calculated based on 3, 3, 10, 5, 8, 6, 8, 8, 9, and 6 significant SNPs. After multivariable adjustment, unweighted and weighted GRS were both associated with cerebrovascular abnormality, WMH volume, FA, and MD of the four sites (right and left corticospinal tracts and cingulate gyri) except for the MD measured using the left cingulate gyrus.

Conclusions: Our study indicated that glucose regulation-associated loci are linked to MRI measures, which may provide novel insights into the presence and progression of brain injury.

Keywords: brain microstructure; cerebrovascular abnormality; glucose‐related genetic risk score; white matter hyperintensity.

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