Polypathologic associations with grey matter atrophy in neurodegenerative disease.

Mixed pathologies are common in neurodegenerative disease; however, antemortem imaging rarely captures copathologic effects on brain atrophy due to a lack of validated biomarkers for non-Alzheimer's pathologies. We leveraged a dataset comprising antemortem MRI and postmortem histopathology to assess polypathologic associations with atrophy in a clinically heterogeneous sample of 125 human dementia patients (41 female, 84 male) with T1-weighted MRI ≤ 5 years before death and postmortem ordinal ratings of amyloid- β , tau, TDP-43, and α -synuclein. Regional volumes were related to pathology using linear mixed effects models; approximately 25% of data were held out for testing. We contrasted a polypathologic model comprising independent factors for each proteinopathy with two alternatives: a model that attributed atrophy entirely to the protein(s) associated with the patient's primary diagnosis; and a protein-agnostic model based on the sum of ordinal scores for all pathology types. Model fits were evaluated using log-likelihood and correlations between observed and fitted volume scores. Additionally, we performed exploratory analyses relating atrophy to gliosis, neuronal loss, and angiopathy. The polypathologic model provided superior fits in training and testing datasets. Tau, TDP-43, and α -synuclein burden were inversely associated with regional volumes, but amyloid- β was not. Gliosis and neuronal loss explained residual variance in and mediated the effects of tau, TDP-43, and α -synuclein on atrophy. Regional brain atrophy reflects not only the primary molecular pathology but also co-occurring proteinopathies; inflammatory immune responses may independently contribute to degeneration. Our findings underscore the importance of antemortem biomarkers for detecting mixed pathology.Significance statement Gross brain atrophy is an essential marker of neurodegenerative disease, relied on both in quantitative research and clinical assessment. Recent autopsy studies show that dementia patients typically have more than one form of neuropathology in their brains, but atrophy is typically ascribed to the presumed pathology associated with patients' primary diagnosis, without consideration of copathologies. The present study related postmortem histopathology to antemortem MRI collected close to death in a clinically heterogeneous sample of dementia patients. We found that polypathology was frequent at the regional level, particularly in limbic cortex. Moreover, we report a significant mediating effect for gliosis on the relationship between protein accumulation and atrophy, suggesting a role for inflammatory immune responses in driving neurodegeneration.