{"doi":"10.1093/brain/awaf418","title":"Imaging and plasma biomarkers for pathological accumulation in Down syndrome","abstract":"Down syndrome is characterized by triplication of chromosome 21, leading to early-onset Alzheimer's disease pathology, with nearly all individuals with Down syndrome developing amyloid and tau pathology. In the new era of amyloid-modifying therapies, it is vital to identify early biomarkers for Alzheimer's disease pathology in Down syndrome. Striatal amyloid may begin to accumulate sooner than cortical amyloid in Down syndrome. Tau phosphorylation at specific sites, including 217, can be quantified in plasma and may represent an important mechanistic step in the development of tau pathology. This study had two aims: (i) to compare the relative age at increase of multiple biomarkers (cortical amyloid, striatal amyloid, plasma pTau217 and summary tau pathology); and (ii) to test whether plasma pTau217 can identify both the current presence and likely future accumulation of amyloid and tau pathology. To identify optimal biomarkers for early intervention, we examined longitudinal cortical and striatal amyloid PET, plasma pTau217 and tau PET in 328 individuals with Down syndrome enrolled in the Alzheimer Biomarker Consortium-Down Syndrome study. To compare the timing of biomarker changes, we modelled longitudinal biomarkers using generalized additive mixed models relative to age. We used receiver operating characteristic curve analysis to identify thresholds for both current and likely future accumulation of amyloid and tau pathology. For all comparisons, we used age as the null model, performing DeLong's tests to evaluate the performance of age relative to biomarker-based prediction. Imaging biomarkers increased at around 40 years old, with plasma pTau217 increasing somewhat later than the three PET biomarkers. Striatal amyloid increased before cortical amyloid in some participants; however, this was not uniform across individuals. If an individual was classified as a reliable accumulator with one biomarker, he or she was likely to be a reliable accumulator in other biomarkers. Age was as sensitive as plasma pTau217 in its ability to both detect preclinical Alzheimer's disease pathology and predict near future accumulation of both amyloid and tau. These results suggest that all adults with Down syndrome should be screened for Alzheimer's disease pathology starting shortly before age 40 years and considered for clinical trials. Age alone was as effective at detecting both current pathology and likely future accumulation as plasma pTau217. Because this disease is so closely concurrent with age in individuals with Down syndrome, plasma pTau217 may not provide more diagnostic benefits than age.","journal":"Brain","year":2025,"id":535335,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"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":1419431,"name":"Ziqiao Jiao","orcid":null,"position":1,"is_corresponding":false},{"id":460292,"name":"James T. Kennedy","orcid":null,"position":2,"is_corresponding":false},{"id":329924,"name":"Ann D. Cohen","orcid":"0000-0001-7395-9624","position":3,"is_corresponding":false},{"id":760519,"name":"Zinayida Schlachetzki","orcid":null,"position":4,"is_corresponding":false},{"id":328913,"name":"Melissa Petersen","orcid":"0000-0002-6543-1819","position":5,"is_corresponding":false},{"id":270459,"name":"Benjamin L. Handen","orcid":"0000-0001-9550-1665","position":6,"is_corresponding":false},{"id":270461,"name":"Bradley T. Christian","orcid":"0000-0002-9653-559X","position":7,"is_corresponding":false},{"id":80305,"name":"Mark Mapstone","orcid":"0000-0003-0280-8057","position":8,"is_corresponding":false},{"id":270470,"name":"H. Diana Rosas","orcid":"0000-0001-9360-7511","position":9,"is_corresponding":false},{"id":270467,"name":"Florence Lai","orcid":"0000-0003-4354-0624","position":10,"is_corresponding":false},{"id":270463,"name":"Joseph H. Lee","orcid":"0000-0002-2000-4821","position":11,"is_corresponding":false},{"id":270468,"name":"Sharon J. Krinsky‐McHale","orcid":"0000-0002-7205-7319","position":12,"is_corresponding":false},{"id":245004,"name":"Frederick A. Schmitt","orcid":"0000-0003-4315-2488","position":13,"is_corresponding":false},{"id":888599,"name":"Jordan P. Harp","orcid":"0000-0003-2089-0883","position":14,"is_corresponding":false},{"id":374097,"name":"Christy Hom","orcid":"0000-0003-0266-0961","position":15,"is_corresponding":false},{"id":270460,"name":"Ira T. Lott","orcid":"0000-0002-3107-0752","position":16,"is_corresponding":false},{"id":270471,"name":"Sigan L. Hartley","orcid":"0000-0002-0186-6282","position":17,"is_corresponding":false},{"id":232613,"name":"Shahid Zaman","orcid":"0000-0003-1639-6014","position":18,"is_corresponding":false},{"id":366601,"name":"Lauren T. Ptomey","orcid":"0000-0002-1705-1643","position":19,"is_corresponding":false},{"id":68016,"name":"Jeffrey M. Burns","orcid":"0000-0001-7609-8954","position":20,"is_corresponding":false},{"id":270464,"name":"Dana Tudorascu","orcid":"0000-0003-4675-3692","position":21,"is_corresponding":false},{"id":17647,"name":"Laura Ibáñez","orcid":"0000-0003-2381-7059","position":22,"is_corresponding":false},{"id":34920,"name":"Michael S. Rafii","orcid":"0000-0003-2640-2094","position":23,"is_corresponding":false},{"id":270466,"name":"Elizabeth Head","orcid":"0000-0003-1115-6396","position":24,"is_corresponding":false},{"id":226074,"name":"Beau M. Ances","orcid":"0000-0003-3862-7397","position":25,"is_corresponding":false},{"id":310966,"name":"Julie K. 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