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

Acta Neuropathol Commun. 2020 Nov 19;8(1):196. doi: 10.1186/s40478-020-01072-8.


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.

Keywords: APOE; Alpha-synuclein; Amyloid beta; GWAS; Parkinson disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / metabolism*
  • Apolipoprotein E4 / genetics
  • Apolipoproteins E / genetics*
  • Brain / metabolism*
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mendelian Randomization Analysis
  • Middle Aged
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Peptide Fragments / cerebrospinal fluid
  • Peptide Fragments / metabolism*
  • Phosphorylation
  • alpha-Synuclein / cerebrospinal fluid
  • alpha-Synuclein / metabolism
  • tau Proteins / cerebrospinal fluid
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • Apolipoproteins E
  • MAPT protein, human
  • Peptide Fragments
  • SNCA protein, human
  • alpha-Synuclein
  • amyloid beta-protein (1-42)
  • tau Proteins