Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.

BACKGROUND: Neurodegenerative diseases have traditionally been classified by their predominant protein pathology. However, accumulating evidence reveals extensive molecular cross-talk between distinct pathological proteins, particularly in Alzheimer's disease (AD). OBJECTIVE: This review examines cross-disease protein interactions and their implications for diagnosis and treatment. METHODS: We systematically reviewed peer-reviewed literature published between 2020 and 2025, complemented by seminal earlier studies, examining molecular mechanisms of protein cross-seeding, clinical evidence of co-pathology, and emerging therapeutic strategies. RESULTS: Cross-seeding between amyloid-β (Aβ), tau, α-synuclein, and TDP-43 has been demonstrated in vitro and in vivo. Harmonized autopsy studies reveal that 91% of individuals over 80 years harbor multiple neuropathologies. Co-pathology accelerates cognitive decline and complicates biomarker interpretation. Anti-amyloid immunotherapies lecanemab and donanemab demonstrate 27-35% slowing of cognitive decline, while anti-tau antibodies targeting N-terminal epitopes have uniformly failed, prompting investigation of combination approaches. CONCLUSIONS: Recognition of cross-disease protein interactions necessitates a paradigm shift toward multi-target therapeutic strategies and precision medicine approaches accounting for individual co-pathology burden.