Comparative analysis of brain-derived tau oligomer interactomes in Alzheimer's disease, non-demented with Alzheimer's neuropathology, and primary age-related tauopathy: Implications for neurodegeneration and cognitive resilience

Background: In Alzheimer's disease (AD), soluble tau oligomers are central to neurodegeneration and cognitive decline. Resilient individuals, such as those with non-demented Alzheimer's neuropathology (NDAN) or primary age-related tauopathy (PART), offer critical insights into protective mechanisms against tau-mediated neurodegeneration. NDAN individuals exhibit AD neuropathology without cognitive impairment or neurodegeneration, while PART, characterized by hippocampal- and entorhinal-restricted tau pathology, manifests with minimal-to-no amnestic changes. Brain-derived tau oligomers (BDTO) from these cohorts provide a unique platform to explore molecular pathways underlying both vulnerability and resilience to tau pathology. Objective: To identify vulnerability- and resilience-associated pathways by comparing BDTO interactomes across AD, NDAN, and PART. Methods: BDTO were isolated from AD (n = 4; 2M, 2F), NDAN (n = 4; 2M, 2F), and PART (n = 4; 1M, 3F) hippocampal autopsy specimens using co-immunoprecipitation. Proteins were identified via liquid chromatography-tandem mass spectrometry, and non-specific interactors were filtered using SAINTq. Interactome networks and enrichment analyses were performed using Metascape. Findings were cross-referenced with the Neuropro database and existing literature on tangle-associated proteins. Key interactors were validated through reverse co-immunoprecipitation. Results: A total of 203 proteins were identified, including eight novel interactors not previously linked to AD. All interactomes were enriched in proteins related to tau physiology and lysosomal degradation. NDAN and PART interactomes showed unique enrichment in proteins involved in cellular responses to reactive oxygen species. Conclusions: One vulnerability-associated and 18 resilience-associated pathways that may mitigate tau-mediated neurodegeneration were identified, laying the groundwork for novel diagnostic and therapeutic strategies targeting pathological tau oligomers.