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.