Molecular fragment characteristics and distribution of tangle associated TDP-43 (TATs) and other TDP-43 lesions in Alzheimer’s disease

TAR DNA binding protein 43 (TDP-43) pathology is a defining feature of frontotemporal lobar degeneration (FTLD). In FTLD-TDP there is a moderate-to-high burden of morphologically distinctive TDP-43 immunoreactive inclusions distributed throughout the brain. In Alzheimer’s disease (AD), similar TDP-43 immunoreactive inclusions are observed. In AD, however, there is a unique phenomenon of neurofibrillary tangle-associated TDP-43 (TATs) whereby TDP-43 intermingles with neurofibrillary tangles. Little is known about the characteristics and distribution of TATs, or how burden and distribution of TATs compares to burden and distribution of other FTLD-TDP-like lesions observed in AD. Here we characterize molecular fragment characteristics, burden and distribution of TATs and assess how these features compare to features of other TDP-43 lesions. We performed TDP-43 immunohistochemistry with anti-phosphorylated, C-and N-terminal TDP-43 antibodies in 20 high-probability AD cases and semi-quantitative burden of seven inclusion types within five brain regions (entorhinal cortex, subicu-lum, CA1 and dentate gyrus of hippocampus, occipitotemporal cortex). Hierarchical cluster analysis was used to analyze the dataset that consisted of 75 different combinations of neuropathological features. TATs were non-spherical with heterogeneous staining patterns and present in all regions except hippocampal dentate. All three antibodies detected TATs although N-terminal antibody sensitivity was low. Three clusters were identified: Clus-ter-1 had mild-moderate TATs, moderate-frequent neuronal cytoplasmic inclusions, dystrophic neurites, neuronal intranuclear inclusions and fine neurites, and perivascular and granular inclusions identified only with the N-terminal antibody throughout the brain; Cluster-2 had scant TATs in limbic regions and Cluster-3 mild-moder-ate TATs and mild-moderate neuronal cytoplasmic inclusions and dystrophic neurites throughout the brain and moderate fine neurites. Only 17% of cluster 1 cases had the TMEM106b GG (protective) haplotype and 83% had hippocampal sclerosis. Both features differed across clusters (p=0.03 & p=0.01). TATs have molecular character-istics, distribution and burden, and genetic and pathologic associations like FTLD-TDP lesions.