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Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer\u2019s disease. TDP-43, tau and amyloid-\u03b2 have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer\u2019s disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer\u2019s disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration\/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer\u2019s disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer\u2019s disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0\u201316.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (\u223c3 years) in cases of primary age-related tauopathy compared to Alzheimer\u2019s disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer\u2019s disease and primary age-related tauopathy.<\/jats:p>","DOI":"10.1093\/brain\/awaa299","type":"journal-article","created":{"date-parts":[[2020,8,21]],"date-time":"2020-08-21T19:15:30Z","timestamp":1598037330000},"page":"3463-3476","source":"Crossref","is-referenced-by-count":71,"title":["Protein contributions to brain atrophy acceleration in Alzheimer\u2019s disease and primary age-related tauopathy"],"prefix":"10.1093","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-8634","authenticated-orcid":false,"given":"Keith A","family":"Josephs","sequence":"first","affiliation":[{"name":"Department of Neurology (Behavioral Neurology), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Health Science Research (Biostatistics), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D","family":"Weigand","sequence":"additional","affiliation":[{"name":"Department of Health Science Research (Biostatistics), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirubol","family":"Tosakulwong","sequence":"additional","affiliation":[{"name":"Department of Health Science Research (Biostatistics), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4826-5430","authenticated-orcid":false,"given":"Marina","family":"Buciuc","sequence":"additional","affiliation":[{"name":"Department of Neurology (Behavioral Neurology), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Neuroscience (Neuropathology), Mayo Clinic, Jacksonville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience (Molecular Neuroscience), Mayo Clinic, Jacksonville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew L","family":"Senjem","sequence":"additional","affiliation":[{"name":"Department of Radiology (Radiology Research) Mayo Clinic, Rochester, MN, USA"},{"name":"Department of Information Technology, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J","family":"Spychalla","sequence":"additional","affiliation":[{"name":"Department of Radiology (Radiology Research) Mayo Clinic, Rochester, MN, USA"},{"name":"Department of Information Technology, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Knopman","sequence":"additional","affiliation":[{"name":"Department of Neurology (Behavioral Neurology), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley F","family":"Boeve","sequence":"additional","affiliation":[{"name":"Department of Neurology (Behavioral Neurology), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald C","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Neurology (Behavioral Neurology), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E","family":"Parisi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology (Neuropathology), Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-7917","authenticated-orcid":false,"given":"Dennis 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