Objective: To assess the impact of 1) polygenic risk scores (PRS) on monogenic Parkinson’s disease (PD) risk and time to diagnosis and 2) APOE E4 allele dosage on self-reported cognitive impairment in individuals with and without monogenic PD.

Background: Monogenic PD associated with LRRK2 G2019S and GBA1 N370S mutations exhibits variable phenotypic expression. Polygenic background and APOE E4 allele status may contribute to this variability, but their effects remain unclear in monogenic PD.

Method: This population-based study analyzed data from 35,163 PD cases and 7.5 million participants without PD from the 23andMe Research Cohort and Fox Insight Genetic Substudy. PRS for PD was calculated from established GWAS, and APOE E4 dosage was determined using genotyping. Self-report questionnaires assessed cognitive/memory impairment and hallucinations. Accelerated failure time models estimated the effects of PRS and carrier status (LRRK2/GBA1) on time to PD diagnosis. Logistic regression models examined the effect of PRS and monogenic carrier status on PD risk, and the association of APOE E4 and cognitive, memory, and psychiatric outcomes. All models adjusted for sex and education, and PRS models additionally adjusted for 10 genetic ancestry principal components. Participants less than 40 years of age at study entry were excluded.

Results: Greater polygenic risk was associated with increased monogenic PD penetrance, accelerating the time to PD diagnosis across all carrier groups (TR=.921 [.920 .923], p<.001). Relative to non-carriers with median PRS, having a PRS in the top quartile increased the odds of developing PD 45-fold for dual carriers, 22-fold for LRRK2 G2019S carriers, 5-fold for GBA1 N370S carriers, and twice for non-carriers. APOE E4 dosage conferred an additive risk for cognitive/memory impairment and hallucinations in PD; each additional E4 allele increased the odds of reporting these symptoms by 16-30%. APOE E4 and LRRK2/GBA1 PD carrier status did not interact, suggesting independent contributions to cognitive decline.

Conclusion: PRS modifies PD risk and time to diagnosis among LRRK2 and GBA1 mutation carriers. APOE E4 dosage increases cognitive/memory and psychiatric symptoms independent of LRRK2/GBA1 carrier status. These findings highlight the potential of PRS to refine cohort selection for neuroprotective trials and improve precision in monitoring cognitive outcomes in monogenic PD.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-polygenic-background-and-apoe-e4-in-monogenic-and-idiopathic-parkinsons-disease/