Psychiatric and behavioral disorders in Parkinson’s disease: co-pathogenic mechanisms of tau, Aβ, and α-synuclein proteins (narrative review)

Parkinson's disease (PD) is a common neurodegenerative disorder affecting middle-aged and elderly individuals. Its clinical manifestations include both motor and non-motor symptoms. Traditionally, Lewy bodies (LBs), which are formed by misfolded α-synuclein (α-syn), have been regarded as the core pathological hallmark. It is believed that the selective damage to dopaminergic neurons in the nigrostriatal system by LBs constitutes the primary mechanism underlying motor symptoms. However, approximately 30-80 % of PD patients also experience psychiatric and behavioral disturbances, such as anxiety, depression, cognitive impairment, and sleep disorders. The pathological mechanisms underlying these symptoms cannot be fully explained by α-syn alone. Recent biomarker studies have confirmed that hyperphosphorylated tau protein forms neurofibrillary tangles (NFTs) and amyloid β-protein (Aβ) plaques can coexist with α-syn in the brains of PD patients, especially in advanced stages. These coexisting pathologies show significant positive correlations with cognitive impairment and sleep disorders, suggesting that the neuropsychiatric symptoms in PD may result from the synergistic effects of multiple protein pathologies involving α-syn, tau, and Aβ. This review synthesizes these findings to propose an integrated "synergistic co-pathogenic network" of α-syn, tau, and Aβ, thereby providing a novel theoretical framework for developing precise, multi-target therapeutic strategies against PD-related neuropsychiatric disorders.