Prodromal non-motor symptom trajectories preceding Parkinson disease diagnosis: a retrospective matched case-control study using the All of Us Research Program

Parkinson disease (PD) is preceded by a prodromal phase characterized by non-motor features and subtle motor changes that may appear years before clinical diagnosis. We conducted a retrospective matched case-control study using the All of Us Registered Tier dataset (Curated Data Repository version R2025Q4R6). Cases required 2 or more distinct PD diagnosis dates and age 40 years or older; each was matched to 4 controls without PD by sex and birth year, and 9 prodromal non-motor features were ascertained from condition records before the index date.

Feature concept sets were generated by name-based discovery over standard SNOMED condition concepts with descendant expansion, audited per concept, and are reported in full. Associations were estimated with conditional logistic regression; K-means clustering was applied as an exploratory analysis. The cohort comprised 2673 cases and 10,692 matched controls (mean age 66.8 years; 61.2% male).

REM sleep behavior disorder (RBD) showed the strongest association with PD (odds ratio [OR] 9.68; 95% CI 5.89 to 15.90), followed by mild cognitive impairment (MCI) (OR 4.10; 3.09 to 5.46), orthostatic hypotension (OR 1.83; 1.46 to 2.30), constipation (OR 1.30; 1.14 to 1.49), urinary dysfunction (OR 1.27; 1.12 to 1.44), depression (OR 1.23; 1.09 to 1.39), and anxiety (OR 1.19; 1.05 to 1.35). Insomnia was not associated (OR 0.98; 0.85 to 1.12). Erectile dysfunction showed a statistically significant inverse association (OR 0.83; 0.72 to 0.97) that was unstable across sensitivity analyses and is interpreted as differential ascertainment rather than a protective effect.

Estimates for RBD, MCI, and orthostatic hypotension were stable across ten sensitivity analyses, including three alternative MCI concept definitions and restriction to levodopa-treated cases; depression and anxiety attenuated to the null under levodopa restriction. Overall discrimination was modest (concordance 0.58; area under the curve 0.585). In this large, diverse US cohort, RBD, MCI, and orthostatic hypotension were the prodromal non-motor features most strongly associated with subsequent PD diagnosis; EHR-documented non-motor features are informative at the group level but limited as individual-level predictors.

We gratefully acknowledge the All of Us Research Program participants for their contributions, and the National Institutes of Health's All of Us Research Program for making the participant data available. This research used data from the All of Us Research Program of the National Institutes of Health; the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Generative artificial intelligence (Claude, Anthropic) was used to assist with development and review of statistical analysis code and with drafting and editing of the manuscript text; all study design decisions, data extraction, statistical analyses, verification of results, and interpretation were performed by the authors, who take full responsibility for the content of this article.

No dedicated funding was received for this research. Florida Atlantic University, Charles E. Schmidt College of Medicine, Boca Raton, FL, USA Meet Popatbhai Kachhadia, Sameea Husain Wilson & Marc A.