Disease-specific tangle immunophenotypes distinguish hippocampal vulnerability in Alzheimer’s disease and Parkinson’s disease dementia

INTRODUCTION Tau pathology typically occurs in Alzheimeŕs disease (AD), however is also frequently present in Parkinsońs disease dementia (PDD) and Dementia with Lewy Bodies (DLB), yet its disease-specific signature is unclear.

Methods

Five tau, amyloid-β, α-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.

Results

AT8, 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-β and α-synuclein remained conserved.

Discussion

Disease-specific tau signatures vary across hippocampal subregions and neuronal populations, implicating the contribution of regional and cell-specific factors beyond pathology burden.