Neuropathological measures of increased tau phosphorylation across the Down syndrome lifespan
Individuals with Down syndrome (DS) have an increased risk of developing Alzheimer disease (AD), with nearly all individuals exhibiting AD neuropathology, including amyloid beta (Aβ) plaques and neurofibrillary tangles (NFT), by age 40 years. Fluid AD biomarker studies highlight an increase in several phosphorylated tau (p-tau) epitopes in DS. However, neuropathological measures of p-tau epitopes in DS have not been examined. Therefore, our main objective was to characterize p-tau epitope burdens across the DS lifespan at autopsy. We analyzed postmortem brain samples of 98 individuals with late-onset AD (LOAD), DS with AD neuropathology (DSAD), young DS (below 40 years of age), and age-matched neurotypical controls, ranging from 1 to 96 years of age. Immunohistochemical and digital pathology measures of p-tau epitopes at threonine 181 (pThr181), threonine 217 (pThr217), and threonine 231 (pThr231) burdens in the frontal cortex were compared across groups. We observed similar pThr181, pThr217, and pThr231 burdens between DSAD and LOAD, despite DSAD cases being younger on average. Observed pThr181, pThr217, and pThr231 burdens were higher in DSAD compared to young DS and neurotypical controls. Generalized additive models (GAMs) were used to model the cross-sectional trajectory of p-tau epitope burdens across the DS lifespan. Estimated age breakpoints revealed a significant rise in frontal cortex pThr231 at age 40, followed by pThr181 and pThr217 at age 42. In summary, our findings revealed an age-associated increase in p-tau epitopes across the DS lifespan. Our results have the potential to inform future associations between neuropathological and biofluid and neuroimaging biomarker measures of p-tau epitopes.
Authors
- Amrita K. Cheema (ORCID: https://orcid.org/0000-0003-4877-7583)
- Wayne Silverman (ORCID: https://orcid.org/0000-0002-7842-8600)
- Peter Bulova
- Forest Lai (ORCID: https://orcid.org/0000-0003-0159-7673)
- Jesse R. Pascual (ORCID: https://orcid.org/0000-0002-3307-0887)
- Li Liu (ORCID: https://orcid.org/0000-0003-3022-936X)
- Elizabeth Andrews (ORCID: https://orcid.org/0000-0003-1131-5983)
- Sierra Wright
- Halyma Nguyen
- Lorena Sordo (ORCID: https://orcid.org/0000-0002-7016-6706)
- Lisi Flores Aguilar (ORCID: https://orcid.org/0000-0002-7962-7433)
- Michael Phelan
- William Charles Kreisl
- Eric Doran
- Phong T. Ngo
- Joseph Hyungwoo Lee
- Lawrence Honig
- Deborah Pang
- Dana L. Tudorascu
- Sigan L. Hartley
- Mark Mapstone
- David Keator
- Ira T. Lott
- Lauren Ptomey
- Patrick Lao
- Bradley T. Christian
- Jeremy Rouanet
- Sterling C. Johnson
- Nicole Schupf
- Michael A. Yassa
- Sid O’Bryant
- Fan Zhang
- Herminia Diana Rosas
- Christy L. Hom
- Victoria Lupson
- Charles Laymon
- Michael S. Rafii
- Davneet Singh Minhas
- Badri Varadarajan
- Benjamin L. Handen
- Isabel Rivera
- Shahid Zaman
- Isabel Clare
- Rameshwari Tumuluru
- M Ilyas Kamboh
- Rasmus M. Birn
- Kewei Chen
- Denise Head
- Alan Hoang
- Tatiana M. Foroud
- Neelesh Nadkarni
- Julia K. Kofler
- Jordan Harp
- Frederick Schmitt
- Sharon J. Krinsky-McHale
- Beau M. Ances
- Adam M. Brickman
- Karen Bell
- Jeff Burns
- Melissa Petersen
- Elizabeth Head
- Howard F. Andrews
- Margaret Pulsifer
- Julie C. Price
- Ann D. Cohen
- Milos D. Ikonomovic
Institutions
- Brigham and Women's Hospital (US)
- University of Wisconsin–Madison (US)
- Harvard University (US)
- University of Kentucky (US)
- University of Pittsburgh (US)
- University of California, Irvine (US)
- Washington University in St. Louis (US)
- Massachusetts General Hospital (US)
- Geriatric Research Education and Clinical Center (US)
- VA Pittsburgh Healthcare System (US)
Publication Details
- Journal
- Acta Neuropathologica
- Published
- 2026-03-22
- DOI
- https://doi.org/10.1007/s00401-026-02994-8
- Primary Topic
- Down syndrome and intellectual disability research
- Type
- article
- Field-Weighted Citation Impact
- 0.00