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

Abstract

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 beta1–42, 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 beta1–42 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 beta1–42 (R2 = 2.29%; p = 2.5 × 10−11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1–42 levels (p = 7.3 × 10−04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1–42 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 beta1–42 (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 beta1–42, and APOE.

Polygenic Risk Scores Contribute to Personalized Medicine of Parkinson’s Disease

“…Several studies have examined the associations between PD PRS and these CSF biomarkers. Two studies conducted by Ibanez et al, [24,52], and one study by Li et al [25] did not find an association between PRS and CSF α-syn, while Lee et al [53] found that higher PD PRS was associated with lower CSF α-syn. Notably, Ibanez et al [52] found that PD PRS was correlated with CSF Aβ42 and PD cases with higher PRS present lower CSF Aβ42 levels, indicating that PD development and accumulation of Aβ42 in the brain may share similar pathways.…”

Proteinopathy and Longitudinal Cognitive Decline in Parkinson Disease

“…Specifically, TaqMan assays (Applied Biosystems, Waltham, MA) for rs429358 (ABI#C_3084793_20) and rs7412 (ABI#C_904973_10) were used, as we previously published. 34 ABI Sequence Detection software was used to detect the 6 combinations of APOE e2, e3, and e4.…”