Objective: To assess the impact of genetic burden in Parkinson’s disease (PD) progression over 5 years.

Background: Individual genetic variants have been shown to influence longitudinal PD progression; however, the effect of overall genetic burden—reflecting the combined impact of multiple high-risk alleles—on PD progression remains unclear.

Method: We enrolled patients with early PD who were within one year of diagnosis and categorized them into high or low genetic burden groups based on the median of the polygenic risk score (PRS). The PRS was constructed from five SNPs identified in Asian GWAS (SNCA, LRRK2, PARK16, ITPKB, SV2C), selected for having the largest effect sizes and genome-wide significance (p < 5×10^-8) in the latest Asian GWAS meta-analysis, providing an individual quantitative measure of genetic burden. Non-motor symptoms (NMS) were assessed annually using the Non-Motor Symptoms Scale (NMSS), Hospital Anxiety and Depression Scale (HADS), and Epworth Sleepiness Scale (ESS). Disease severity and motor progression were evaluated annually using Hoehn and Yahr (H&Y) staging, the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III motor score, and the Postural Instability and Gait Difficulty (PIGD) score. Cognitive progression was assessed annually using five standardized cognitive test scores. Annual progression rates for all longitudinal outcomes were estimated using linear mixed-effects models with random intercepts.

Results: We included 205 patients with PD: 105 in the low-PRS group (below the median of PRS) and 100 in the high-PRS group (above the median). Compared with the low-PRS group, the high-PRS group had a significantly lower annual progression rate in the NMSS total score (2.195 vs 5.951, p=0.042) and NMSS Domain 9 (Miscellaneous) score (0.285 vs 1.469, p=0.015). The high-PRS group also showed significantly slower deterioration in the cognitive memory domain (−0.009 vs 0.096, p=0.038). All estimates were derived from linear mixed-effects models adjusted for confounders and corrected for multiple comparisons.

Conclusion: PD patients with high genetic burden exhibited a slower decline in non-motor and cognitive functions, particularly in memory performance. These findings suggest that the selected PRS may have a protective effect in PD patients over time.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-cumulative-genetic-risk-score-predicts-progression-in-parkinsons-disease-5-year-longitudinal-study-from-the-early-parkinsons-disease-longitudinal-singapore-pals-cohort/