Longitudinal white matter integrity alterations as a function of Preclinical Alzheimer’s Pathology: findings from the EPAD non‐demented cohort

Abstract

AbstractBackgroundCross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progression.We investigated trajectories of WM alterations in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort and their relationship with AD biomarkers.MethodEPAD inclusion criteria were age>50 years and Clinical Dementia Rating≤0.5. We selected participants with baseline CSF samples, and longitudinal DTI scans. After defining AT groups(Ingala et al. 2021), A‐T+ participants were excluded (final N = 283).MRI acquisition and preprocessing was previously described(Lorenzini et al. 2022). We extracted fractional anisotropy (FA) in 14 regions(Mori et al. 2005) from DTI as a marker of WM integrity. Site harmonization of MRI‐derived data was performed with ComBat toolbox(Fortin et al. 2018).Age‐ and sex‐corrected linear mixed models with random intercepts on participants were used to estimate time‐effect on MRI‐derived phenotypes, and their interaction with AT status. Results were corrected for multiple testing.ResultAt baseline, A+T‐ participants showed lower FA in body/columns (ß = ‐0.04, p<0.01) and crus of fornix (ß = ‐0.01, p = 0.04), and in splenium (ß = ‐0.007, p = 0.04) and body of CC (ß = ‐0.01, p = 0.03) compared to A‐T‐. In the whole group, FA decreased over time in splenium (ß = ‐0.003, p<0.01), body (ß = ‐0.002, p<0.01) and genu of CC (ß = ‐0.009, p<0.01), body/columns (ß = ‐0.004, p<0.01) and crus of fornix (ß = ‐0.005, p<0.01), and inferior longitudinal fasciculus (ß = ‐0.007, p<0.01). Compared to A‐T‐, A+T+ participants showed steeper FA reduction in superior (Interaction:ß = ‐0.004, p = 0.03) and anterior corona radiata (Interaction:ß = ‐0.006, p = 0.02).ConclusionOur results suggest that WM integrity in key AD regions may degenerate early in the AD continuum, showing greater impairment over short‐time intervals in individuals with higher AD‐specific pathological burden.