{"doi":"10.1016/j.nbas.2025.100139","title":"Testing the causal impact of plasma amyloid on total Tau using a genetically informative sample of adult male twins","abstract":"The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes t-Tau was observed. Instead, the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau, though our use of total rather than phosphorylated tau was a limitation. In contrast, Aβ biomarkers appeared to causally impact NFL in cognitively unimpaired men in their late 60 s.","journal":"Aging Brain","year":2025,"id":566119,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":228673,"name":"Michael C. Neale","orcid":"0000-0003-4887-659X","position":1,"is_corresponding":false},{"id":279709,"name":"Matthew S. Panizzon","orcid":null,"position":2,"is_corresponding":false},{"id":585576,"name":"Ruth McKenzie","orcid":"0000-0001-6973-4174","position":3,"is_corresponding":false},{"id":245704,"name":"Xin Tu","orcid":"0000-0001-6470-980X","position":4,"is_corresponding":false},{"id":486272,"name":"Hong Xian","orcid":"0000-0002-7549-4880","position":5,"is_corresponding":false},{"id":228607,"name":"Chandra A. Reynolds","orcid":"0000-0001-6502-7173","position":6,"is_corresponding":false},{"id":264628,"name":"Michael J. Lyons","orcid":"0000-0001-6516-9219","position":7,"is_corresponding":false},{"id":230262,"name":"Robert A. Rissman","orcid":"0000-0001-9245-8278","position":8,"is_corresponding":false},{"id":486270,"name":"Jeremy A. Elman","orcid":"0000-0002-5840-1769","position":9,"is_corresponding":false},{"id":264626,"name":"Carol E. Franz","orcid":"0000-0002-8987-1755","position":10,"is_corresponding":false},{"id":264627,"name":"William S. Kremen","orcid":"0000-0002-8629-5609","position":11,"is_corresponding":false},{"id":14684,"name":"Nathan A. Gillespie","orcid":"0000-0001-8655-2823","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-19T02:56:36.440192Z","pmid":"40487291","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":[]}