Cognitive Performance in Prodromal Neuronal α Synuclein Disease

Importance: Cognitive abnormalities may emerge during prodromal neuronal a-synuclein disease (NSD), but their domain specificity and longitudinal course are uncertain. Objective: To characterize baseline cognition and longitudinal change in prodromal NSD compared with healthy controls, NSD-negative genetic carriers, and sporadic Parkinson disease (PD). Design: Longitudinal cohort study using Parkinson's Precision Medicine Initiative (PPMI) data, with first visits from July 2010 through April 2026 and up to 4 years of follow-up. Setting: Multicenter cohort. Participants: Healthy controls (HC; n=244), GBA1 or LRRK2 nonmanifesting carriers without NSD (n=323), prodromal NSD participants recruited through hyposmia or isolated rapid eye movement sleep behavior disorder cohorts (n=1640), and sporadic PD (n=824). Exposures: NSD status and clinical cohort. Main Outcomes and Measures: Cognitive summary scores for verbal memory, executive function, processing speed, language, and visuospatial function, and PPMI-defined mild cognitive impairment (MCI). Models adjusted for age, sex, education, and APOE ε4 status. Results: Among 3031 participants (mean [SD] age, 66.6 [7.0] years; 1322 female [43.6%]), prodromal NSD participants had lower baseline verbal-memory performance than HC (adjusted difference, −0.20 SD; 95% CI, −0.34 to −0.07; adjusted P = .007); NSD-negative genetic carriers did not differ from HC. No other cognitive domain was lower than HC at baseline or longitudinally. In the primary age-adjusted analysis, verbal-memory trajectory differed from HC over 4 years (P = .009), whereas in a smaller age-matched sensitivity subset through year 3, it did not (P = .62); the baseline difference persisted (adjusted difference, −0.28 SD; 95% CI, −0.46 to −0.10; P = .003). Adjusted MCI probability increased from 10.2% to 15.1% in prodromal NSD, compared with 8.4% to 5.0% in HC and 13.4% to 17.7% in PD. The increase was greater than in HC (ratio of annual odds ratios, 1.28; 95% CI, 1.04 to 1.58; adjusted P = .04) but not PD (P = .62). Conclusions and Relevance: Prodromal NSD was associated with modestly lower verbal memory and increasing MCI probability relative to HC, without lower performance in other cognitive domains. The baseline verbal-memory difference was robust, whereas the longitudinal trajectory finding was not reproduced in the smaller age-matched sensitivity subset.