White Matter Microstructural Alterations Mediate the Association between Polygenic Risk for Alzheimer’s Disease and Cognitive Performance in Clinically Asymptomatic Adults

Abstract

Purpose: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder influenced by genetic factors, with a long preclinical phase characterized by subtle alterations in brain microstructure. Although the apolipoprotein E ε4 allele is a well-established genetic risk factor, AD is increasingly recognized as a polygenic condition. However, how polygenic risk manifests in white matter (WM) microstructure and cognition remains unclear. This study aims to investigate the associations between AD polygenic risk scores (ADPRS), WM microstructure, and cognitive performance in clinically asymptomatic adults.

Methods: Data from 36400 individuals (aged 45–83 years) in the UK Biobank were analyzed. Diffusion tensor imaging and neurite orientation dispersion and density imaging metrics were extracted from 48 WM tracts. General linear models were used to examine associations between ADPRS, WM integrity, and 10 cognitive measures. Mediation analyses were conducted to test whether WM microstructure mediated the relationship between ADPRS and cognitive performance.

Results: Higher ADPRS was significantly associated with reduced fractional anisotropy and intracellular volume fraction, and with increased mean, axial, and radial diffusivity, as well as isotropic volume fraction across limbic and association fibers, particularly in the cingulum hippocampus, fornix, posterior thalamic radiation, and superior fronto-occipital fasciculus. Higher ADPRS was also associated with poorer cognitive performance, most prominently on tests of executive function (Trail Making Test B), episodic memory (Paired Associate Learning), and processing speed (Symbol Digit Substitution). Mediation analysis revealed that WM microstructural alterations, especially increased radial diffusivity and reduced fractional anisotropy in the posterior thalamic radiation, partially mediated the association between ADPRS and cognitive performance, accounting for up to 4.88% of the total effect.

Conclusion: ADPRS is linked to selective WM microstructural alterations and subtle cognitive difference in clinically asymptomatic adults. WM microstructural changes partially mediate the association between ADPRS and cognitive performance.