Distinct molecular patterns of TDP-43 pathology in Alzheimer's disease: relationship with clinical phenotypes

The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer's disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43^409/410, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43^403/404) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as AD^TDP + FL because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43⁴⁰⁹, pTDP-43^409/410). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as AD^{TDP + CTF}. Ten AD cases did not contain any TDP-43 pathology and were referred to as AD^TDP-. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of AD^{TDP + CTF} cases, 63,6% of AD^TDP + FL and 100% of the AD^TDP- cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of AD^TDP + FL, in 16,6% of the AD^{TDP + CTF}, and in none of the AD^TDP- cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from AD^TDP- to AD^{TDP + CTF} and AD^TDP + FL with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in AD^TDP + FL cases.