TDP-43 DRIVES FASTER RATES OF HIPPOCAMPAL ATROPHY IN ALZHEIMER’S DISEASE STARTING AT LEAST 10 YEARS PRIOR TO DEATH

Abstract

Autopsy studies have not found an association between beta-amyloid or tau and rates of hippocampal atrophy in Alzheimer's disease. TAR DNA binding protein of 43kDa (TDP-43) has been linked to Alzheimer's disease yet no studies have assessed for an association between TDP-43 and rates of hippocampal atrophy. Two-hundred ninety-eight autopsied cases with Alzheimer's spectrum disease that had antemortem head MRI scans were analysed for this study. TDP-43 immunohistochemistry and staging was performed and cases classified as follows: no TDP-43; TDP-43 restricted to amygdala; and TDP-43 spreading into hippocampus. Eight-hundred seventeen MRI scans, spanning 1.0–11.2 years prior to death, were available for analysis. We utilized two independent neuroimaging techniques to calculate hippocampal volume on all serial MRI available for each case (longitudinal FreeSurfer and tensor-based morphometry with symmetric normalization (TBM-SyN)) and performed linear mixed-effects regression models to estimate the association between TDP-43 and rate of hippocampal atrophy, accounting for NIA-Alzheimer's Association neurofibrillary tangle stage, and determine the trajectory of TDP-43 associated atrophy. In addition we determined whether higher NIA-Alzheimer's Association neurofibrillary tangle stage was associated with faster rates of hippocampal atrophy accounting for TDP-43. One-hundred forty-one cases showed no TDP-43, 33 had TDP-43 restricted to the amygdala and 124 had TDP-43 in hippocampus. Cases with hippocampal TDP-43 had faster rates of hippocampal atrophy compared to cases with amygdala-only TDP-43 and those without any TDP-43 in cases with an intermediate-high likelihood of having Alzheimer's disease. The trajectory analysis suggested that increased rates of TDP-43 associated hippocampal atrophy could be detected at least 10-years before death (Figure). Results were similar for FreeSurfer and TBM-SyN. Higher NIA-Alzheimer's Association neurofibrillary tangle stage was only associated with faster rates when TDP-43 was absent.