Investigating tau-related white matter degeneration in Alzheimer's disease using fixel-based analysis

Alzheimer's disease involves the accumulation of amyloid-β and tau proteins, with tau-related white matter degeneration potentially contributing to cognitive impairment. This study investigated the relationship between regional tau deposition and white matter degeneration using fixel-based analysis and examined whether white matter changes mediate tau-related cognitive decline. We analyzed data from 285 participants in the Alzheimer's Disease Neuroimaging Initiative, classified based on amyloid and tau biomarker status into four groups: 141 amyloid-negative tau-negative cognitively unimpaired (A - T - CU), 58 amyloid-positive tau-negative cognitively unimpaired (A + T - CU), 49 amyloid-positive tau-positive mild cognitive impairment (A + T + MCI), and 37 amyloid-positive tau-positive dementia (A + T + Dementia). Fixel-based analysis metrics included fiber density, log-transformed fiber-bundle cross-section, and their combined measure derived from diffusion MRI. These were evaluated in relation to ¹⁸F-flortaucipir tau PET standardized uptake value ratios and multiple cognitive assessments. Results showed that A + T + MCI and A + T + Dementia participants exhibited significantly reduced fixel-based metrics in subcortical white matter adjacent to cortical regions with high tau deposition, particularly in temporal and frontal areas (FDR-corrected p < 0.05), with more widespread reductions in A + T + Dementia. Mediation analysis revealed that white matter degeneration across multiple subcortical white matter regions adjacent to temporal, insular, and parietal cortices significantly and partially mediated the relationship between regional tau deposition and cognitive decline, accounting for 6.3-19.7% of the total effect. These findings suggest that tau-related white matter degeneration in regions adjacent to heavily affected cortical areas partially contributes to cognitive impairment in Alzheimer's disease.