Objective: To determine whether genetic variability constitutes a source of heterogeneity in levels of cerebrospinal fluid (CSF) proteins in patients with Parkinson’s disease (PD) and controls.

Background: CSF protein levels are considered promising biomarkers for early diagnosis of PD. Tremendous heterogeneity has been found in the analysis of CSF proteins in PD patients with a number of covariates being discussed such as age, sample processing and phenotypic variation. Genetic variation may well be another source of heterogeneity.

Methods: In a case-control dataset comprising 122 de novo PD patients and 63 controls from an established longitudinal cohort study, “DeNoPa”, we genotyped the PD risk variants SNCA rs11931074 and SNCA Rep1 as well as APOE rs429358, which has been associated with cognitive decline in neurodegenerative disease. We further measured CSF levels of total and phosphorylated tau protein (tau and p-tau), β-amyloid 1-40 (Aβ40), β-amyloid 1-42 (Aβ42) and total α-synuclein (aSyn) in the same individuals.

Results: In PD patients we found significant association of SNCA rs11931074 with CSF tau (Kruskal-Wallis, not corrected for multiple testing, p=0.011) and p-tau (p=0.019). Patients homozygous for the wildtype allele (G/G) had significantly lower levels of CSF tau and p-tau than patients with the G/T genotype. We found a similar association in controls. There was no significant association of rs11931074 with CSF aSyn, Aβ40 or Aβ42 in patients or controls. In PD patients we found significant association of APOE rs429358 with CSF tau (p=0.001), p-tau (p=0.004), Aβ40 (p=0.044), and Aβ42 (p=0.041), but not aSyn (p=0.077). Patients homozygous for the wildtype allele (T/T) had lower levels of tau, p-tau, Aβ40 and higher levels of Aβ42 than patients with the T/C genotype. In controls we only found significant association of rs429358 with Aβ42 (p=0.034) but not tau, p-tau, Aβ40 or aSyn. There was no significant association of SNCA Rep1 with CSF protein levels.

Conclusions: Genetic variation may be another source of heterogeneity in CSF protein levels in PD patients. SNCA rs11931074 is associated with levels of CSF tau and p-tau, APOE rs429358 is associated with levels of CSF tau, p-tau, Aβ40 and Aβ42 in PD patients. Further elucidation of the impact of genetic variation on CSF protein levels is warranted to delineate potential biomarkers for early diagnosis of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-genetic-variation-in-snca-and-apoe-on-cerebrospinal-fluid-protein-levels-in-patients-with-parkinsons-disease-and-controls/