{"doi":"10.1002/alz.70831","title":"Tau mediates the impact of amyloid and vascular disease burden on the trajectory of clinical symptoms","abstract":"INTRODUCTION: Amyloid (A) and vascular (V) pathologies often co-occur and progress over decades. We leveraged chronicity, defined as the years above a biomarker-positivity threshold, to examine how the timing of A and V relates to cognitive decline. METHODS: We modeled Clinical Dementia Rating-Sum of Boxes (CDR-SB) trajectories in n = 558 participants with [C-11] Pittsburgh compound B positron emission tomography (PET), magnetic resonance imaging-derived white matter hyperintensities (WMHs), and longitudinal CDR assessments. In n = 500 with MK6240 PET, we tested whether tau mediates A-V associations with CDR-SB in a moderated mediation framework. RESULTS: Whether biomarker \"burden\" was modeled as chronicity (A+years, V+years), or estimated amyloid and WMH at CDR visits, significant interactions showed a synergistic effect of WMHs and amyloid on accelerated CDR-SB trajectories. Tau significantly mediated these associations. DISCUSSION: Operationalizing chronicity clarifies how long individuals have exceeded A and V thresholds and improves clinical interpretability. WMH accumulation exacerbates amyloid-related cognitive decline. Longitudinal tau imaging could further inform staging and intervention timing. HIGHLIGHTS: Longer amyloid (A) and vascular disease (V) chronicity were associated with faster cognitive decline, emphasizing the importance of considering chronic exposure to these pathologies. Individuals with higher V burden experienced a steeper decline in cognition in the presence of A pathology, highlighting the interaction between V and neurodegenerative processes. Progression from early to mild dementia was faster with greater white matter hyperintensity chronicity, even when A duration was held constant, supporting the idea that V pathology amplifies the clinical impact of amyloid in Alzheimer's disease. Tau accumulation played a significant mediating role in linking A and V burden to cognitive decline, suggesting that tau pathology is a critical downstream factor in symptom progression. Person-level chronicity estimates of A and V provide a more precise understanding of cognitive decline trajectories, offering insights for early intervention strategies.","journal":"Alzheimer s & Dementia","year":2025,"id":548113,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9371,"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":289687,"name":"Rebecca L. Koscik","orcid":"0000-0003-0025-744X","position":1,"is_corresponding":false},{"id":289691,"name":"Bruce P. Hermann","orcid":"0000-0003-0133-4427","position":2,"is_corresponding":false},{"id":289689,"name":"Erin M. Jonaitis","orcid":"0009-0004-5091-8255","position":3,"is_corresponding":false},{"id":289688,"name":"Tobey J. Betthauser","orcid":"0000-0001-8856-1352","position":4,"is_corresponding":false},{"id":389939,"name":"Leonardo A. Rivera‐Rivera","orcid":"0000-0001-5629-8721","position":5,"is_corresponding":false},{"id":289692,"name":"Karly Alex Cody","orcid":"0000-0001-5996-2560","position":6,"is_corresponding":false},{"id":289693,"name":"Nathaniel A. Chin","orcid":"0000-0001-8008-9356","position":7,"is_corresponding":false},{"id":371950,"name":"Robert V. Cadman","orcid":"0000-0001-7685-1977","position":8,"is_corresponding":false},{"id":284436,"name":"Kevin M. Johnson","orcid":"0000-0003-0479-4242","position":9,"is_corresponding":false},{"id":908195,"name":"Aaron S. Field","orcid":"0000-0003-4349-1009","position":10,"is_corresponding":false},{"id":1254558,"name":"Sanjay Asthana","orcid":"0000-0002-3298-6324","position":11,"is_corresponding":false},{"id":389938,"name":"Laura Eisenmenger","orcid":"0000-0001-6764-4239","position":12,"is_corresponding":false},{"id":861881,"name":"Bradley Christian","orcid":"0000-0001-5072-3512","position":13,"is_corresponding":false},{"id":230038,"name":"Sterling C. Johnson","orcid":"0000-0002-8501-545X","position":14,"is_corresponding":false},{"id":340627,"name":"Lianlian Du","orcid":null,"position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41164853","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":[]}