Objective: This study evaluates the association between a distal regulatory haplotype at the SNCA locus and cognitive performance, measured by the Montreal Cognitive Assessment (MoCA), in individuals with PD.

Background: PD shows marked heterogeneity in clinical progression, particularly in cognition, with up to 80% of patients developing dementia. The genetic architecture of PD includes both rare high-penetrance mutations and common variants influencing disease risk and clinical variability. The SNCA locus on chromosome 4q22.1, encoding alpha-synuclein, is a major genetic risk locus for sporadic PD. While duplications and triplications cause aggressive forms with early cognitive decline, regulatory variants in non-coding regions may exert subtler effects on neuronal resilience and cognitive preservation.

Method: GP2 Release 11 genomic and clinical data were analyzed in the secure Verily Workbench. The cohort included 8,534 PD individuals of European ancestry with complete MoCA, age, and sex data. Variants in a distal regulatory region upstream of SNCA (chr4:88–92 Mb, GRCh38) were extracted using PLINK2, identifying three SNPs in near-complete linkage disequilibrium. A haplotype dosage score (SNCA_score) was calculated. Linear regression models adjusted for age, sex, and genotype principal components included a genotype–age interaction.

Results: Three SNPs in a distal SNCA regulatory region (88 Mb) were in near-complete linkage disequilibrium (r = 0.998–0.999), forming a haplotype block (reference allele frequency 93.5%). Each additional copy of the major haplotype (SNCA_score) was associated with higher cognitive performance (β = 0.3416, p = 0.001; ~0.34 MoCA points per allele). Age (β = −0.0868, p < 0.001) and male sex (β = −0.4600, p < 0.001) were associated with lower performance. A positive SNCA_score–age interaction was observed (β = 0.027, p = 0.009).

Conclusion: Genetic variation in distal regulatory elements of the SNCA locus is associated with cognitive performance in PD. The interaction with age suggests the protective effect of this haplotype strengthens with aging, consistent with a role in cognitive resilience. These findings highlight distal SNCA regulatory variation as a contributor to cognitive heterogeneity in PD and support its potential for patient stratification in studies of disease progression and neuroprotective therapies.

Table 1. Cohort characteristics

Table 2. Variant and haplotype

Table 3. Regression model results

Figure 1. Genomic Region Plot

Figure 2. Age X SNCA haplotype

References: 1. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment (MoCA): a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-9.
2. Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson’s disease. Lancet Neurol. 2020;19(2):170-8.
3. Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC, Barrasa MI, et al. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates gene expression. Nature. 2016;533(7601):95-9.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-determinants-of-cognitive-performance-in-parkinsons-disease-impact-of-distal-regulatory-variation-at-the-snca-locus-in-the-gp2-cohort/