{"doi":"10.1002/ana.26588","title":"Polygenic Effect on Tau Pathology Progression in Alzheimer's Disease","abstract":"OBJECTIVE: Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar-tau accumulation as a key driver of dementia symptoms is unclear. METHODS: We combined the to-date largest number of genetic risk variants of AD (n = 85 lead single-nucleotide polymorphisms [SNPs]) from recent genome-wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau-positron emission tomography (PET), amyloid-PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid-PET, we predicted the rate of tau-PET increases in Braak-stage regions-of-interest and cognitive decline. We also assessed PGS-risk enrichment effects on the required sample size in clinical trials targeting tau pathology. RESULTS: We found that a higher PGS was associated with higher rates of tau-PET accumulation, in particular at elevated amyloid-PET levels. The tau-PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%. INTERPRETATION: Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023;93:819-829.","journal":"Annals of Neurology","year":2022,"id":270500,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8394,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":12184,"name":"Simon Frerich","orcid":"0000-0002-8275-6113","position":1,"is_corresponding":false},{"id":302170,"name":"Rainer Malik","orcid":"0000-0001-9212-2520","position":2,"is_corresponding":false},{"id":84338,"name":"Nicolai Franzmeier","orcid":"0000-0001-9736-2283","position":3,"is_corresponding":false},{"id":613835,"name":"Alfredo Ramı́rez","orcid":"0000-0003-4991-763X","position":4,"is_corresponding":false},{"id":12191,"name":"Martin Dichgans","orcid":"0000-0002-0654-387X","position":5,"is_corresponding":false},{"id":67599,"name":"Michael Ewers","orcid":"0000-0001-5231-1714","position":6,"is_corresponding":false},{"id":637345,"name":"Alzheimer's Disease Neuroimaging Initiative (ADNI)","orcid":null,"position":7,"is_corresponding":false},{"id":232092,"name":"Anna Rubinski","orcid":"0000-0002-1768-1231","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T00:27:31.019242Z","pmid":"36571564","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":[]}