{"doi":"10.1186/s40478-020-01072-8","title":"Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease","abstract":"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 beta 1–42 , total tau, and phosphorylated tau 181 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 tau 181 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 (R 2 = 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 .","journal":"Acta Neuropathologica Communications","year":2020,"id":68731,"datarank":0.47032413238937254,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.0,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9447,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":365492,"name":"Jorge A. Bahena","orcid":null,"position":1,"is_corresponding":false},{"id":17613,"name":"Chengran Yang","orcid":"0000-0003-4577-5590","position":2,"is_corresponding":false},{"id":250204,"name":"Umber Dube","orcid":"0000-0001-9324-1927","position":3,"is_corresponding":false},{"id":242337,"name":"Fabiana Farias","orcid":"0000-0002-5215-7304","position":4,"is_corresponding":false},{"id":27622,"name":"John Budde","orcid":"0000-0001-7778-7276","position":5,"is_corresponding":false},{"id":365493,"name":"Kristy Bergmann","orcid":null,"position":6,"is_corresponding":false},{"id":365494,"name":"Carol Brenner-Webster","orcid":null,"position":7,"is_corresponding":false},{"id":27593,"name":"John C. Morris","orcid":"0000-0001-9820-5618","position":8,"is_corresponding":false},{"id":308303,"name":"Richard J. Perrin","orcid":"0000-0002-3443-7716","position":9,"is_corresponding":false},{"id":232093,"name":"Nigel J. Cairns","orcid":"0000-0001-9858-3344","position":10,"is_corresponding":false},{"id":364141,"name":"John O’Donnell","orcid":"0000-0003-0486-778X","position":11,"is_corresponding":false},{"id":364142,"name":"Ignacio Álvarez","orcid":"0000-0002-8537-3935","position":12,"is_corresponding":false},{"id":230758,"name":"Mónica Díez-Fairén","orcid":"0000-0003-1882-0309","position":13,"is_corresponding":false},{"id":365495,"name":"Miquel Aguilar","orcid":null,"position":14,"is_corresponding":false},{"id":250208,"name":"Rebecca L. Miller","orcid":"0000-0002-1227-5891","position":15,"is_corresponding":false},{"id":250202,"name":"Albert A. Davis","orcid":"0000-0003-2042-8445","position":16,"is_corresponding":false},{"id":27628,"name":"Pau Pástor","orcid":"0000-0002-7493-8777","position":17,"is_corresponding":false},{"id":250211,"name":"Paul T. Kotzbauer","orcid":"0000-0001-7155-114X","position":18,"is_corresponding":false},{"id":271861,"name":"Meghan C. Campbell","orcid":"0000-0003-3030-9669","position":19,"is_corresponding":false},{"id":52686,"name":"Joel S. Perlmutter","orcid":"0000-0003-3263-8917","position":20,"is_corresponding":false},{"id":229257,"name":"Hervé Rhinn","orcid":null,"position":21,"is_corresponding":false},{"id":27580,"name":"Oscar Harari","orcid":"0000-0002-2635-6975","position":22,"is_corresponding":false},{"id":230680,"name":"Carlos Cruchaga","orcid":"0000-0002-0276-2899","position":23,"is_corresponding":false},{"id":230679,"name":"Bruno A. Benítez","orcid":"0000-0002-2699-3878","position":24,"is_corresponding":false},{"id":17647,"name":"Laura Ibáñez","orcid":"0000-0003-2381-7059","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:41:52.279368Z","pmid":"33213513","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}