The tau biomarker cascade is condensed in Down syndrome compared to sporadic Alzheimer's disease

Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium - Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.

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Publication Details

Journal
Brain
Published
2025-11-14
DOI
https://doi.org/10.1093/brain/awaf428
Citations
2
Primary Topic
Down syndrome and intellectual disability research
Type
article
Field-Weighted Citation Impact
3.76
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article

The tau biomarker cascade is condensed in Down syndrome compared to sporadic Alzheimer's disease

Howard Andrews, Julia Kofler, Margaret B. Pulsifer, Dana Tudorascu et al.
2 citations
Brain
Down syndrome and intellectual disability research
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article

The tau biomarker cascade is condensed in Down syndrome compared to sporadic Alzheimer's disease

Howard Andrews, Julia Kofler, Margaret B. Pulsifer, Dana Tudorascu, Lawrence S. Honig, Amrita K. Cheema, Badri Varadarajan, Lauren T. Ptomey, Benjamin L. Handen, Charles M. Laymon, Tobey J. Betthauser, Sharon J. Krinsky‐McHale, Bradley Christian, Frederick A. Schmitt, Wayne Silverman, Joseph H. Lee, Neelesh Nadkarni, Rasmus M. Birn, Miloš D. Ikonomović, Ann D. Cohen, Brecca Bettcher, Denise Head, Michael S. Rafii, Christy Hom, Victoria Lupson, Andrew K McVea, Patrick J. Lao, Rameshwari V. Tumuluru, Rachael E. Wilson, Finnuella J. Carey, Nicole Schupf, Karly Alex Cody, Matthew Zammit, Karen Bell, Tatiana Foroud, Jacob Morse, Oskar Hansson, Hailey Bruzzone, Peter Bulova, Shahid Zaman, H. Diana Rosas, Sigan L. Hartley, Sid E. O’Bryant, Alexandra H DiFilippo, Max McLachlan, Florence Lai, Elizabeth Head, Davneet Minhas, I. C. H. Clare, Julie C. Price, Jordan P. Harp, Beau M. Ances, Mark E. Mapstone, Michael A. Yassa, M. Ilyas Kamboh, Jeff Burns, Ira T. Lott, David B. Keator, Kewei Chen, Fan Zhang, Weiquan Luo, Bradley T. Christian, Melissa Petersen, Rebecca E. Langhough, Sterling C. Johnson, Shorena Janelidze, Mark Mapstone, H. Diana Rosas, William Charles Kreisl, Eric Doran, Adam M Brickman, Deborah Pang
article en
2 citations

Abstract

Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium - Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.

Brain
University of Wisconsin–Madison (US), Harvard University (US), University of Pittsburgh (US), Lund University (SE), University of California, Irvine (US), Washington University in St. Louis (US), University of Cambridge (GB), Columbia University Irving Medical Center (US), New York State Office for People With Developmental Disabilities (US), Massachusetts General Hospital (US), Cambridge Intellectual Property (United Kingdom) (GB)
Openalex Percentile: Top 6%
Down syndrome and intellectual disability research
3.76
DOIOpen Access PDFOpenAlex
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