AbstractBackgroundBrain atrophy, particularly of the hippocampus and amygdala, is thought to reflect the effects of neurodegenerative proteinopathies such as TAR DNA‐binding protein‐43 (TDP‐43) and Alzheimer’s disease neuropathologic change (ADNC). We sought to test this hypothesis in a cohort of oldest‐old participants.MethodWe used data from participants in The 90+ Study, a study of aging and dementia in individuals aged 90 and older, with both MRI during life and autopsy. Our outcome variables were hippocampus and amygdala volumes calculated from computational anatomy toolbox (CAT12, http://www.neuro.uni‐jena.de/cat/). Proteinopathy variables were dichotomized: TDP‐43 (presence in hippocampus/neo‐cortex), ADNC (NIA‐AA high severity), and Lewy bodies (LB, limbic/neocortical involvement). We examined the association between presence of the proteinopathies and gray matter atrophy using three different methods. First, we compared the volumes between those with vs. without each neuropathology. Then we studied the association between the volumes and proteinopathies in a model containing all neuropathologies, adjusting for age and intracranial volume. Lastly, we calculated voxel‐wise multiple linear regressions of gray matter atrophy across the whole brain (using CAT12) and report results for each proteinopathy. We also repeated the above analyses including cognitive impairment status for comparison.ResultTable‐1 summarizes participant characteristics (N=64). Group differences in hippocampal and amygdala volumes were in the low‐to‐moderate effect‐size range for TDP‐43 (hippocampus d=0.40, amygdala d=0.33) and ADNC (hippocampus d=0.38, amygdala d=0.54, Figure‐1). For associations incorporating all three proteinopathies, semi‐partial correlations were low for TDP‐43 (hippocampus sr=‐0.15, amygdala sr=‐0.10) and ADNC except for the amygdala (hippocampus sr=‐0.12, amygdala sr=‐0.25, Table‐2). For the voxelwise analysis of gray matter atrophy, none of the proteinopathies displayed strong associations (Figure‐3). Generally, LB showed no discernible effect on gray matter atrophy. In contrast to the modest results for the proteinopathies, cognitive impairment was strongly associated with medial temporal atrophy (Figure‐4).ConclusionIn this sample of oldest‐old participants, TDP‐43 and ADNC were only modestly associated with atrophy of the hippocampus and amygdala. While this finding may partly due to low number of participants, strong association of atrophy with cognitive status in the same sample suggests mere presence of degenerative proteinopathies might not be sufficient for brain tissue loss.