Cognitive impairment in Parkinson’s disease (PD) poses a significant societal challenge. PD affects more than 1% of people aged 65 and older, with 24–31% developing dementia and another 26% experiencing mild cognitive impairment. As populations age, the impact of PD-related cognitive decline is expected to grow.
Recent research has advanced our understanding of the mechanisms and biomarkers associated with cognitive impairment in PD. Studies have examined the epidemiology and natural history of cognitive decline, including prodromal stages and the overlap with Lewy body dementia.
Key pathophysiological mechanisms include aggregation and prion-like propagation of α-synuclein, co-existing pathologies, synaptic dysfunction, genetic factors, neuroinflammation, mitochondrial dysfunction, oxidative stress, microbiome changes, degeneration of cholinergic and monoaminergic systems, autonomic dysfunction, altered neuronal network activity, and glymphatic impairment. Fluid and neuroimaging biomarkers, alongside preclinical models and pathological studies, are providing new insights into these processes.
A better understanding of these multifaceted mechanisms may explain the variability in cognitive profiles and disease progression, paving the way for personalized, disease-modifying therapies.
Key Points
While Alzheimer’s disease, vascular dementia, and mixed brain pathologies remain leading causes of dementia, cognitive impairment in PD and other parkinsonism disorders is increasingly recognized.
Cognitive decline in PD is heterogeneous, likely reflecting differences in α-synuclein aggregation and its distribution in brain regions linked to cognition.
Alzheimer’s co-pathology is common in PD and may worsen cognitive impairment, potentially interacting with α-synuclein, though the precise mechanisms remain unclear.
Neuroinflammation, microbiome alterations, mitochondrial dysfunction, and oxidative stress can increase extracellular α-synuclein, activating microglia and triggering synaptic dysfunction and progressive neurodegeneration.
Additional contributing factors include lysosomal dysfunction, deficits in cholinergic and monoaminergic systems, cardiovascular autonomic dysfunction, disrupted synaptic and network activity, altered brain connectivity, and glymphatic dysfunction.
Advances in research support a multidisciplinary, personalized approach to diagnosing and managing cognitive impairment in PD, aiming to improve patient outcomes and quality of life for both patients and caregivers.
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