Objective: To investigate the disease progression between SNCA rs6826785 C allele carriers and noncarriers over 5 years.

Background: A genome-wide association study-linked variant (SNCA rs6826785) was shown to have protective effect of cognitive performance among PD patients in our previous study. SNCA rs6826785 could be a novel therapeutic target for PD. However, evidence on the longitudinal outcomes of SNCA rs6826785 carriers remains unknown. We hypothesize that PD patients carrying SNCA rs6826785 may experience a slower progression rate.

Method: Early PD patients diagnosed within one year were categorized into SNCA rs6826785 variant carriers and non-carriers. Non-motor symptom progression was evaluated using the Non-Motor Symptom Scale (NMSS), while cognitive progression was assessed across five cognitive domains annually. A longitudinal linear mixed model was used to compare changes in NMSS total and domain scores, as well as cognitive domain performance, between the two groups. To account for multiple comparisons, the false discovery rate (FDR) method was applied, and q-values were calculated, with a significance threshold set at 0.1.

Results: A total of 193 PD patients, including 163 SNCA rs6826785 carriers and 30 non-carriers were assessed prospectively over a 5-year period. SNCA rs6826785 carriers, compared to noncarriers, had a significantly lower progression rate in NMSS score (carriers vs non-carriers: 2.195 vs 5.951, p=0.047, q=0.047), NMSS domain 4 score (carriers vs non-carriers: 0.088 vs 0.709 p=0.0152, q=0.045) and NMSS domain 9 score (carriers vs non-carriers: 0.285 vs 1.469, p=0.018, q=0.028). SNCA carriers also exhibited significantly slower deterioration in cognitive language domain (carriers vs non-carriers: -0.009 vs: 0.096 vs -0.06, p=0.016, q=0.082) after adjustment for confounders and multiple comparisons.

Conclusion: Carriers of the SNCA rs6826785 variant exhibited a slower decline in non-motor and cognitive functions, particularly in perceptual processing and language performance. These findings suggest that SNCA carriers may have a protective effect in PD patients over time, highlighting SNCA as a potential therapeutic target.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-gwas-linked-snca-carriers-show-slower-non-motor-and-cognitive-progression/