Progression of fiber bundle damage in amnestic Alzheimer’s disease and LATE: a 2-year fixel-based study

Alzheimer's disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) are two neurodegenerative diseases underpinned by distinct proteinopathies, which share a similar initial amnestic clinical phenotype but have a different clinical course. Some pathophysiological models suggest a role for white matter (WM) fiber bundles in disease progression, but they remain discussed, as does their applicability to LATE. Using longitudinal fixel-based analysis, we investigated the progression of WM fiber bundle alterations over 2 years in early amnestic AD (n = 16; clinical-biological diagnosis based on CSF biomarkers and amyloid/tau PET imaging), probable LATE (n = 12; diagnosis based on recently published diagnostic criteria), and amyloid-negative controls (n = 15). We explored the associations between baseline and longitudinal WM fiber bundle alterations and (i) cognitive/functional decline in both patient groups and (ii) baseline amyloid and tau load in patients with AD. In both AD and LATE, we found a 2-year progression of WM fiber bundle alterations in temporo-parietal and temporo-frontal tracts, most of which were altered at baseline, and to a lesser extent in the temporopulvinar bundle of Arnold. We also found a differential 2-year progression of the alterations according to pathology, affecting temporal, limbic tracts and the cingulum in AD, and bilateral superior longitudinal fasciculi in LATE. Low metrics within these fiber bundles at baseline were associated with a more rapid cognitive decline. We found only weak associations between WM fiber bundle alterations and baseline amyloid and tau PET. These results suggest a functional role for WM fiber bundle alterations in the progression of cognitive impairment, making this parameter a potential predictive marker of cognitive decline.