Disease-specific tangle immunophenotypes distinguish hippocampal vulnerability in Alzheimers disease and Parkinsons disease dementia

Structured AbstractINTRODUCTION Tau pathology typically occurs in Alzheime[r]s disease (AD), however is also frequently present in Parkinso[n]s disease dementia (PDD) and Dementia with Lewy Bodies (DLB), yet its disease-specific signature is unclear. METHODSFive tau, amyloid-{beta}, -synuclein and neuronal markers were analysed across hippocampal subfields in non-demented controls (CTLs), AD, PDD and DLB using multiplex immunohistochemistry, single-tangle classification and confocal imaging. RESULTSAT8, pTau217, and GT38 were predominatly detected in AD, while pS422 was enriched in PDD and pS396 showed a region- and disease-specific pattern. DLB resembled AD in subregional tau distribution. Tau marker correlation were different comparing AD, PDD and CTL. Single-tangle analyses revealed disease-specific immunophenotypes but conserved mature intra-tangle epitope organisation. Distinct tau signatures were associated with inhibitory interneuron vulnerability, while regional tau co-occurrence with amyloid-{beta} and -synuclein remained conserved. DISCUSSIONDisease-specific tau signatures vary across hippocampal subregions and neuronal populations, implicating the contribution of regional and cell-specific factors beyond pathology burden.