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 two 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. We also found a differential 2-year progression of the alterations according to pathology, affecting temporal and limbic tracts in AD, and the ventral section of the superior longitudinal fasciculus in LATE. Low metrics within these fiber bundles at baseline were associated with a more rapid cognitive decline. We found no association between WM fiber bundle alterations and baseline tau-PET and only weak associations with amyloid-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.