Biomarkers

The Alzheimer's disease (AD) field has shifted toward a biological definition based on the deposition of amyloid-β1-42 (Aβ1-42) and phosphorylated-Tau181 (p-Tau181), yet only a subset of Aβ1-42-positive individuals progresses to AD. The variability in the brain's susceptibility to AD pathology may arise from the effect of polygenic pathways and their interaction with Aβ1-42 and p-Tau181 deposition. Here, we explored the effect of pathway-specific polygenic risk scores (PRSs), AD pathology, and their interaction on WM fiber density (FD) and fiber cross-section (FC) using a fixel-based approach.

We analyzed 803 non-demented participants from the European Prevention of Alzheimer's Dementia (EPAD) cohort (age 64.7±7.3 years, 57.0% females, 34.2% APOE4 carriers, Table 1) who underwent genome sequencing, CSF Aβ1-42 and p-Tau181 measurements, and structural and diffusion MRI. Bellenguez PRSs were constructed using 85 genetic variants associated with AD. After excluding those mapping to APOE loci, genetic variants were grouped based on biological function into 6 pathway-specific PRSs (i.e., amyloid, clearance, immune activation, inflammation, migration and signal transduction pathways). FD and FC were computed from diffusion MRI and averaged within WM bundles. Linear models were used to assess the effect of pathway-specific PRSs, Aβ1-42 and p-Tau181, and their interactions on WM, at the bundle and fixel levels. Models were corrected for age, sex, total intracranial volume, and APOE-ε4 carriership. p-values were adjusted for multiple comparisons using the false discovery rate method.

P-Tau181 showed both increasing and decreasing effects on FD, indicating a multiphasic relationship. The migration pathway was linked to greater FD and FC primarily in the left hemisphere, aligning with hemispheric dominance (Figure 1). Pathology-dependent effects of pathway-PRSs were observed. Aβ1-42 moderated the effect of the clearance pathway on FD, with a positive slope in A+ compared to A- individuals (Figure 2A). p-Tau181 moderated the effect of the immune activation pathway on FD, with a negative slope in T+ compared to T- individuals (Figure 2B).

Polygenic risk for AD influences WM integrity both directly and via AD pathology-dependent effects. Genetic susceptibility to preclinical AD pathology activates distinct biological processes that differentially affect WM integrity.