When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases

Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are becoming increasingly prevalent in today's aging population and with significant cost to society. While these diseases were traditionally defined by distinct protein aggregates, namely, tau tangles and amyloid-β (Aβ) plaques in AD and α-synuclein (α-syn) inclusions in PD, substantial evidence reveals frequent mixed pathologies, with tau, α-syn, and Aβ aggregates coexisting in patients. This copathology complicates understanding disease mechanisms, classification, and progression, highlighting the need to examine mixed pathologies in neurodegenerative diseases to develop disease-modifying therapies. The presence of mixed proteinopathies suggests shared or converging pathological mechanisms, including synergistic aggregation, enhanced seeding capabilities, and shared protein-protein interactions. Understanding these molecular mechanisms is essential for identifying disease modifiers and refining experimental models. This review explores the pathogenic mechanisms of α-syn and tau individually, followed by exploration of their molecular interactions and potential mechanisms of coaggregation and exacerbation of pathology. By recognizing the intersection of these pathologies, further research can refine disease classifications for neurodegenerative diseases.