Uncovering α-synuclein and tau burden in Alzheimer's and Lewy body diseases

Neurodegenerative diseases are classified based on their histopathological hallmarks alongside their clinical manifestations. Alzheimer's disease and Lewy body disease, which includes Parkinson's disease, are traditionally referred to as tauopathy and synucleinopathy, respectively. However, much like how Alzheimer's disease can present with Parkinsonian features and Parkinson's disease with cognitive impairment, there is considerable overlap in their underlying pathology. In this study, we applied antibodies specific for disease-related, post-translationally modified epitopes in α-synuclein and tau to post-mortem brain tissue from 16 Alzheimer's disease and 9 Lewy body disease cases with a focus on the substantia nigra and the locus coeruleus. We demonstrate the presence of inclusion pathology comprised of carboxy-terminally truncated α-synuclein in the substantia nigra and locus coeruleus of Alzheimer's disease cases that is not revealed with standard post-mortem screening. These findings suggest that α-synuclein pathology in Alzheimer's disease can be significantly underestimated. Additionally, we observed abundant tau pathology in the substantia nigra of Alzheimer's disease cases at levels often exceeding those seen in Lewy body disease, despite the absence of a movement disorder diagnosis in Alzheimer's disease cases. Furthermore, the connection between regional tau pathology and associated clinical impairment may be region-dependent, where some tau pathology may be, at least temporally, innocuous.