Characteristics and mechanisms of cognitive impairment in Parkinson disease

Cognitive impairment in people with Parkinson disease (PD) imposes a substantial societal burden: PD affects over 1% of the population aged 65 years and older, and 24-31% of individuals with this condition develop dementia and another 26% present with mild cognitive impairment. Given the increasing prevalence of PD in light of an ageing population, the challenge of PD-associated cognitive impairment is likely to intensify. In this Review, we highlight the latest research advances in PD-associated cognitive impairment, emphasizing emerging mechanistic insights and new biomarkers. We outline the epidemiology and natural history of cognitive decline in PD, focusing on prodromal stages and the closely related spectrum of Lewy body dementia. We discuss key pathophysiological factors and mechanisms, including aggregation and prion-like propagation of α-synuclein; co-pathologies; synaptic dysfunction; genetics; neuroinflammation; mitochondrial dysfunction; oxidative stress; microbiome alterations; degeneration of cholinergic and monoaminergic systems; autonomic dysfunction; altered neuronal network activity; and glymphatic impairment. We consider how advances in fluid and neuroimaging biomarkers, together with preclinical disease models and pathological studies, are providing insights into these mechanisms. A deeper understanding of the multifaceted pathophysiology of PD-associated cognitive impairment will help us to explain the heterogeneity of cognitive profiles and disease progression in PD, providing a foundation for personalized disease-modifying treatments.