Distinguishing the contribution of tau and TDP-43 pathologies to medial temporal lobe atrophy and cognitive decline in Alzheimer’s disease

Details

Supervisors

Hanseeuw, Bernard

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Alzheimer’s disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) both affect the medial temporal lobe (MTL), causing cognitive decline that can progress to dementia. LATE affects 40% of the general population at the average age of death (80–85 years) and up to 74% of AD cases. Distinguishing pure AD from AD with comorbid LATE is challenging because there are no effective in vivo TDP-43 biomarkers, and both diseases present similar clinical symptoms. However, differential diagnosis is crucial as new disease-modifying therapies develop. Interestingly, MTL subregions, such as the hippocampus and amygdala, are heterogenous structures that can be subdivided into amygdala subnuclei and hippocampal subfields, suspected to show varying vulnerability to tau or TDP-43 pathologies. In this work, we aimed to distinguish the contributions of tau and TDP-43 pathologies to MTL atrophy and cognitive decline in AD. We first integrated neuropathological data with antemortem MRI. We then combined these data with cognitive measures to identify a distinct cognitive profile associated with TDP-43 inclusions in AD patients. First, we segmented the entorhinal (ERC) and parahippocampal cortices (PHC), with amygdala subnuclei and hippocampal subfields. We assessed associations between MTL substructure volumes and tau or TDP-43 pathologies, conducted cross-sectional analyses of MTL volumes stratified by pathology levels, and performed longitudinal analyses comparing MTL atrophy rates based on tau levels or TDP-43 pathology. Second, we analyzed cognitive performance using different neuropsychological tests, stratified by tau and TDP-43 pathology levels, and performed longitudinal analyses to compare cognitive decline based on tau levels or TDP-43 pathology. Our imaging analyses revealed an anterior-posterior gradient in the MTL, with TDP-43 pathology predominantly affecting the anterior MTL (amygdala and hippocampal head), while tau pathology was more associated with the posterior MTL (PHC). In terms of cognitive performance, no distinct cognitive signature was observed in AD with TDP-43 inclusions. Taken together, our results suggest that hippocampal head atrophy could serve as a biomarker to differentiate AD from AD with TDP-43 inclusions. In addition, more specific neuropsychological tests targeting hippocampal head function should be developed to further distinguish between these two conditions. Although TDP-43 pathology does not appear to have a differentiated cognitive impact in untreated populations, evaluating its presence in patients treated with upcoming anti-amyloid therapies will be of utmost importance, as individuals older than 80 have not been included in clinical trials.