Toward common treatment strategies: convergent proteinopathies and mitochondrial dysfunction in Alzheimer’s and Parkinson’s diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegenerative disorders (ND) globally, disproportionately affecting the elderly population. Traditionally viewed as distinct diseases, AD is defined by symptoms of cognitive impairment and dementia with amyloid-β and tau protein pathologies, while PD is defined by motor symptoms and eventual dementia with α-synuclein (α-syn) protein pathology. However, these pathologies are not unique to either disease, with a large fraction of AD patients displaying α-syn inclusions and PD patients displaying abnormal tau. Emerging evidence indicates that pathological tau and α-syn not only frequently coexist in AD and PD, but may engage in synergistic interactions that promote mitochondrial dysfunction, accelerate neurodegeneration, and worsen cognitive decline in both disorders. This review aims to provide both the prevailing views of AD and PD, as well as a detailed discussion of their commonalities with a focus on how tau and α-syn toxicities intersect at the mitochondrial level. Common features of mitochondrial impairment in AD and PD are discussed, including complex I deficiency, oxidative stress, impaired axonal transport, altered mitochondrial dynamics, and mitochondrial DNA damage. While prior reviews have often examined AD and PD independently, this review specifically focuses on the convergent and potentially synergistic interactions between tau and α-syn at the level of mitochondrial dysfunction, highlighting a shared mechanistic framework that may inform unified therapeutic strategies. By studying and understanding the mutual mechanisms underlying neurodegeneration in AD and PD, common treatment strategies can be identified.