Cognitive Performance in Prodromal Neuronal α-Synuclein Disease

Importance

Cognitive abnormalities may emerge during prodromal neuronal α-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.

Key Points