EBioMedicine (Dec 2024)
The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndromeResearch in context
- Laura Xicota,
- Lam-Ha T. Dang,
- Alice Lee,
- Sharon Krinsky-McHale,
- Deborah Pang,
- Lisa Melilli,
- Sid O'Bryant,
- Rachel L. Henson,
- Charles Laymon,
- Florence Lai,
- H. Diana Rosas,
- Beau Ances,
- Ira Lott,
- Christy Hom,
- Bradley Christian,
- Sigan Hartley,
- Shahid Zaman,
- Elizabeth Head,
- Mark Mapstone,
- Zhezhen Jin,
- Wayne Silverman,
- Nicole Schupf,
- Benjamin Handen,
- Joseph H. Lee,
- Howard J. Aizenstein,
- Beau M. Ances,
- Howard F. Andrews,
- Karen Bell,
- Rasmus Birn,
- Adam M. Brickman,
- Peter Bulova,
- Amrita Cheema,
- Kewei Chen,
- Bradley T. Christian,
- Isabel Clare,
- Lorraine Clark,
- Ann D. Cohen,
- John N. Constantino,
- Eric W. Doran,
- Anne Fagan,
- Eleanor Feingold,
- Tatiana M. Foroud,
- Benjamin L. Handen,
- Jordan Harp,
- Sigan L. Hartley,
- Elizabeth Head,
- Rachel Henson,
- Christy Hom,
- Lawrence Honig,
- Milos D. Ikonomovic,
- Sterling C. Johnson,
- Courtney Jordan,
- M.Ilyas Kamboh,
- David Keator,
- William E. Klunk,
- Julia K. Kofler,
- William Charles Kreisl,
- Sharon J. Krinsky-McHale,
- Florence Lai,
- Patrick Lao,
- Charles Laymon,
- Joseph H. Lee,
- Ira T. Lott,
- Victoria Lupson,
- Mark Mapstone,
- Chester A. Mathis,
- Davneet Singh Minhas,
- Neelesh Nadkarni,
- Sid O’Bryant,
- Melisa Parisi,
- Deborah Pang,
- Melissa Pettersen,
- Julie C. Price,
- Margaret Pulsifer,
- Michael S. Rafii,
- Eric Reiman,
- Batool Rizvi,
- H. Diana Rosas,
- Laurie Ryan,
- Frederick Schmitt,
- Nicole Schupf,
- Wayne P. Silverman,
- Dana L. Tudorascu,
- Rameshwari Tumuluru,
- Benjamin Tycko,
- Badri Varadarajan,
- Desiree A. White,
- Michael A. Yassa,
- Shahid Zaman,
- Fan Zhang
Affiliations
- Laura Xicota
- Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Lam-Ha T. Dang
- Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
- Alice Lee
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
- Sharon Krinsky-McHale
- Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
- Deborah Pang
- Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
- Lisa Melilli
- Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Sid O'Bryant
- Institute of Translational Research, University of North Texas Health Sciences Center, Fort Worth, TX, USA
- Rachel L. Henson
- Department of Neurology, Washington University in St. Louis, St. Louis, MO
- Charles Laymon
- Departments of Radiology and Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
- Florence Lai
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
- H. Diana Rosas
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
- Beau Ances
- Department of Neurology, Washington University in St. Louis, St. Louis, MO
- Ira Lott
- Department of Neurology, UC Irvine, Irvine, CA, USA
- Christy Hom
- Department of Neurology, UC Irvine, Irvine, CA, USA
- Bradley Christian
- Waisman Center and Department of Human Development and Family Studies, University of Wisconsin–Madison, Madison, WI, USA
- Sigan Hartley
- Waisman Center and Department of Human Development and Family Studies, University of Wisconsin–Madison, Madison, WI, USA
- Shahid Zaman
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- Elizabeth Head
- Department of Pathology & Laboratory Medicine and Department of Neurology, UC Irvine, Irvine, CA, USA
- Mark Mapstone
- Department of Neurology, UC Irvine, Irvine, CA, USA
- Zhezhen Jin
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA
- Wayne Silverman
- Department of Neurology, UC Irvine, Irvine, CA, USA
- Nicole Schupf
- Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
- Benjamin Handen
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
- Joseph H. Lee
- Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA; Corresponding author. Sergievsky Center, P&S Unit 16, 630 West 168th Street, New York, NY, 10032, USA.
- Howard J. Aizenstein
- Beau M. Ances
- Howard F. Andrews
- Karen Bell
- Rasmus Birn
- Adam M. Brickman
- Peter Bulova
- Amrita Cheema
- Kewei Chen
- Bradley T. Christian
- Isabel Clare
- Lorraine Clark
- Ann D. Cohen
- John N. Constantino
- Eric W. Doran
- Anne Fagan
- Eleanor Feingold
- Tatiana M. Foroud
- Benjamin L. Handen
- Jordan Harp
- Sigan L. Hartley
- Elizabeth Head
- Rachel Henson
- Christy Hom
- Lawrence Honig
- Milos D. Ikonomovic
- Sterling C. Johnson
- Courtney Jordan
- M.Ilyas Kamboh
- David Keator
- William E. Klunk
- Julia K. Kofler
- William Charles Kreisl
- Sharon J. Krinsky-McHale
- Florence Lai
- Patrick Lao
- Charles Laymon
- Joseph H. Lee
- Ira T. Lott
- Victoria Lupson
- Mark Mapstone
- Chester A. Mathis
- Davneet Singh Minhas
- Neelesh Nadkarni
- Sid O’Bryant
- Melisa Parisi
- Deborah Pang
- Melissa Pettersen
- Julie C. Price
- Margaret Pulsifer
- Michael S. Rafii
- Eric Reiman
- Batool Rizvi
- H. Diana Rosas
- Laurie Ryan
- Frederick Schmitt
- Nicole Schupf
- Wayne P. Silverman
- Dana L. Tudorascu
- Rameshwari Tumuluru
- Benjamin Tycko
- Badri Varadarajan
- Desiree A. White
- Michael A. Yassa
- Shahid Zaman
- Fan Zhang
- Journal volume & issue
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Vol. 110
p. 105433
Abstract
Summary: Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium–Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. Findings: For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ40 and Aβ42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. Interpretation: Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. Funding: National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).
