Two distinct molecular patterns of TDP‐43 pathology in cases with Alzheimer’s disease pathology

Background TDP43 is a nuclear protein involved in transcription regulation, which is cleaved, phosphorylated and mislocated to the cytoplasm in pathological conditions. TDP43‐positive neuronal inclusions define frontotemporal lobar degeneration (FTLD‐TDP) and limbic predominant age‐related TDP43 encephalopathy (LATE). Neuronal TDP43 inclusions are also seen in Alzheimer’s disease (AD) brain, in ca. 70% of AD patients. We aimed to investigate the role of TDP43 in the development of AD and whether this role differs from that seen in FTLD‐TDP. Method We selected non‐diseased (n=20), preclinical AD (n=16), neuropathologically‐confirmed AD (n=45), and FTLD‐TDP (n=10) cases. Paraffin‐embedded human brain tissue of the hippocampal formation, amygdala, frontal and occipital cortices was immunohistochemically analyzed with antibodies against pathological phosphorylated TDP43 (pTDP43409/410, pTDP43409 and pTDP43403/404) and the N‐ and C‐terminus of TDP43 (N‐t or C‐t‐TDP43). Result We found that the majority of p‐preAD (n=11) and AD cases (n=34) presented neuronal cytoplasmic inclusions (NCIs) and neurofibrillary tangle‐like material (NFTs) positive for pTDP43, phosphorylated at serines 409/410 but not 403/404. Non‐phosphorylated TDP43 epitopes were absent in these cases, except for single lesions positive for C‐terminal TDP43 epitopes. The remaining AD cases (with full‐blown AD neuropathology) presented a molecular pattern similar to that observed in FTLD‐TDP: NCI, dystrophic neurites or NFTs positive for all TDP43 markers used in this study. We referred to these cases as AD/FTLD. These cases presented either typical AD symptoms, a mix of AD and FTD symptoms, or an FTD clinical picture. The majority of AD cases presented a classical AD clinical phenotype. Conclusion TDP‐43 presents two distinct molecular patterns: one AD‐related pattern, which was associated to clinical AD symptoms; and a second AD/FTLD pattern molecularly similar with FTLD‐TDP lesions, that was associated to an FTD clinical picture.