This narrative review examines the genetic architecture of Parkinson’s disease psychosis (PDP) to clarify pathophysiology, risk, and therapeutic implications. Most PD is idiopathic, but variants in established PD loci and other systems may modulate psychosis risk. Among the more consistent PDP signals are cholecystokinin pathway variants—particularly the CCK −45C>T polymorphism and its interaction with CCKAR—reported mainly in Asian cohorts, and suggestive links with APOE ε4 for earlier-onset hallucinations.
The review highlights major sources of inconsistency—small samples, heterogeneous PDP definitions, cross-sectional designs, ethnic stratification, medication and dementia confounding, and limited autopsy confirmation. Clinically, the authors argue for longitudinal, multiethnic studies with standardized PDP phenotyping, adjustment for dopaminergic exposure and cognition, and genome-wide approaches complemented by gene–environment and pharmacogenetic analyses. Potential applications include risk stratification (eg, earlier counseling for APOE ε4 carriers), tailored dopaminergic dosing, and targeted therapies (eg, testing cholecystokinin analogues or HOMER1-modulating strategies). Established symptomatic treatment remains grounded in receptor pharmacology rather than genotype at present.
Reference: Angelopoulou E, Bougea A, Papageorgiou SG, Villa C. Psychosis in Parkinson’s Disease: A Lesson from Genetics. Genes (Basel). 2022 Jun 20;13(6):1099. doi: 10.3390/genes13061099.
