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.

At the time of their contributions, the following authors were employed by and/or held stock or stock options in 23andMe, Inc.: MJK, MVH, PF, JS, AG, ST, KS, DAH, JYT, SA, LNK.

This study was funded by The Michael J. Fox Foundation for Parkinson's Research.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

23andMe research participants provided informed consent and volunteered to participate in the research online, under a protocol approved by Ethical & Independent (E&I) Review Services--an external IRB that is accredited by the Association for Accreditation of Human Research Protection Programs. As of 2022, E&I Review Services is part of Salus IRB (https://www.versiticlinicaltrials.org/salusirb). Fox Insight Genetic Substudy (FIGS) participants were 18 years or older and provided informed consent via the Fox Insight website (WCG IRB IRB#: 120160179, Legacy IRB#: 14-236, Sponsor Protocol Number: 1, Study Title: Fox Insight) (Gottesman et al., 2024).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Model outputs for all logistic regressions and survival models are provided as eTables. Individual-level data from 23andMe are not publicly available due to participant confidentiality and in accordance with the IRB-approved protocol under which the study was conducted. The Fox Insight Genetic Substudy participant data are available through Fox DEN (https://foxden.michaeljfox.org). No custom code or software was generated as part of the study. Details of all software packages used for data processing and analysis may be found in the "Methods" section.

https://foxden.michaeljfox.org