Monogenic Parkinson’s Disease and the Impact of APOE E4: A Case-Control Study

Importance The lack of information on progression, phenoconversion, and risk of dementia in a large genotyped sample impedes reliable enrichment for early interventional trials in Parkinson’s disease (PD). Objective To investigate PD penetrance, risk, motor/non-motor phenotypes, and APOE allele effects in LRRK2 G2019S and GBA N370S carriers. Design Observational longitudinal case-control self-report survey study. Setting A US population-based study cohort enrolled in the 23andMe, Inc. and Fox Insight Genetic Substudy (FIGS) databases. Participants The total cohort included 7,586,842 participants ( n =35,163 PD; 27% of PD cases from FIGS); 8,791 LRRK2 G2019S carriers (565 with PD), 37,427 GBA N370S carriers (524 with PD), 244 dual carriers (37 with PD), and 7.5 million non-carriers (34,037 with PD). Exposure(s) LRRK2 G2019S, GBA N370S, APOE E2/E3/E4 alleles and PD polygenic risk scores (PRS). Main Outcome(s) and Measure(s) Cumulative incidence of PD was estimated using Kaplan-Meier and accelerated failure time models. Relative odds of developing motor and non-motor symptoms were calculated using logistic regression models according to genetic exposure. Impact of the APOE alleles was estimated in a dose-dependent analysis. Results By the age of 80 years, the cumulative incidence of PD was 43% for dual carriers, 32% for LRRK2 G2019S carriers, 6% for GBA N370S carriers, and 3% for non-carriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. Motor symptoms were similar in LRRK2 G2019S, GBA N370S, and non-carriers with PD. GBA N370S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 G2019S the lowest. APOE E4 dosage was associated with greater odds of developing hallucinations and cognitive decline in addition to carrier status. Conclusions and Relevance Our findings support the use of genetic screening—including LRRK2 G2019S, GBA N370S, APOE E4, and PRS—to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetic risk factors.