Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta_1–42, total tau, and phosphorylated tau₁₈₁ as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta_1–42 levels (effect = − 0.5, p = 9.2 × 10⁻¹⁹). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau₁₈₁ levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta_1–42 (R² = 2.29%; p = 2.5 × 10⁻¹¹). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta_1–42 levels (p = 7.3 × 10⁻⁰⁴). Two-sample Mendelian Randomization revealed that CSF amyloid beta_1–42 plays a role in Parkinson’s disease (p = 1.4 × 10⁻⁰⁵) and age at onset (p = 7.6 × 10⁻⁰⁶), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta_1–42 (p = 3.8 × 10⁻⁰⁶), higher mean cortical binding potentials (p = 5.8 × 10⁻⁰⁸), and higher Braak amyloid beta score (p = 4.4 × 10⁻⁰⁴). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta_1–42, and APOE.