. 2024 Dec:110:105433.

doi: 10.1016/j.ebiom.2024.105433. Epub 2024 Nov 4.

The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Laura Xicota¹, Lam-Ha T Dang², Alice Lee³, Sharon Krinsky-McHale⁴, Deborah Pang⁴, Lisa Melilli¹, Sid O'Bryant⁵, Rachel L Henson⁶, Charles Laymon⁷, Florence Lai⁸, H Diana Rosas⁸, Beau Ances⁶, Ira Lott⁹, Christy Hom⁹, Bradley Christian¹⁰, Sigan Hartley¹⁰, Shahid Zaman¹¹, Elizabeth Head¹², Mark Mapstone⁹, Zhezhen Jin¹³, Wayne Silverman⁹, Nicole Schupf², Benjamin Handen³, Joseph H Lee¹⁴; Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS)

Collaborators, Affiliations

Collaborators

Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS):
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

¹ Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
² 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.
³ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
⁵ Institute of Translational Research, University of North Texas Health Sciences Center, Fort Worth, TX, USA.
⁶ Department of Neurology, Washington University in St. Louis, St. Louis, MO.
⁷ Departments of Radiology and Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
⁹ Department of Neurology, UC Irvine, Irvine, CA, USA.
¹⁰ Waisman Center and Department of Human Development and Family Studies, University of Wisconsin-Madison, Madison, WI, USA.
¹¹ Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹² Department of Pathology & Laboratory Medicine and Department of Neurology, UC Irvine, Irvine, CA, USA.
¹³ Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹⁴ 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. Electronic address: JHL2@cumc.columbia.edu.

PMID: 39500037
PMCID: PMC11570228
DOI: 10.1016/j.ebiom.2024.105433

The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Laura Xicota et al. EBioMedicine. 2024 Dec.

. 2024 Dec:110:105433.

doi: 10.1016/j.ebiom.2024.105433. Epub 2024 Nov 4.

Authors

Collaborators

Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS):
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

¹ Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
² 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.
³ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
⁵ Institute of Translational Research, University of North Texas Health Sciences Center, Fort Worth, TX, USA.
⁶ Department of Neurology, Washington University in St. Louis, St. Louis, MO.
⁷ Departments of Radiology and Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
⁹ Department of Neurology, UC Irvine, Irvine, CA, USA.
¹⁰ Waisman Center and Department of Human Development and Family Studies, University of Wisconsin-Madison, Madison, WI, USA.
¹¹ Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹² Department of Pathology & Laboratory Medicine and Department of Neurology, UC Irvine, Irvine, CA, USA.
¹³ Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹⁴ 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. Electronic address: JHL2@cumc.columbia.edu.

PMID: 39500037
PMCID: PMC11570228
DOI: 10.1016/j.ebiom.2024.105433

Abstract

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).

Keywords: Alzheimer's disease; CSF; Down syndrome; Mosaicism; PET; Plasma biomarkers.

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Conflict of interest statement

Declaration of interests BA is a member of VCID Advisory Board without payment. BH receives funding from National Institute of Child Health and Human Development, Autism Speaks, and Roche Pharmaceuticals. EH has consulted for Alzheon and Cyclotherapeutics and received royalties from Elsevier Press. JHL is part of the external advisory board for the Alzheimer's Disease Resource Center for Minority Aging Research, University of Texas, and for the Center of Life Science, Nazarbayev University, Astana, Kazakhstan. MM is an inventor on patents related to biomarkers of neurodegenerative diseases owned by Georgetown University and the University of Rochester. SH is the vice-chair of the ISTAART Down syndrome PIA. SKM is an employee for the New York State Office for People with Developmental Disabilities (OPWDD) and is a consultant for the NIH grant R01-HD098179. SZ is the chair of the scientific committee of the T21 Research Society receiving paid registration to the biannual meeting. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Zigman W.B., Schupf N., Sersen E., Silverman W. Prevalence of dementia in adults with and without Down syndrome. Am J Ment Retard. 1996;100(4):403–412. - PubMed
1. Papavassiliou P., Charalsawadi C., Rafferty K., Jackson-Cook C. Mosaicism for trisomy 21: a review. Am J Med Genet. 2015;167a(1):26–39. - PubMed
1. Papavassiliou P., York T.P., Gursoy N., et al. The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues. Am J Med Genet. 2009;149a(4):573–583. - PMC - PubMed
1. Shin M., Siffel C., Correa A. Survival of children with mosaic Down syndrome. Am J Med Genet. 2010;152a(3):800–801. - PubMed
1. Zhu J.L., Hasle H., Correa A., et al. Survival among people with Down syndrome: a nationwide population-based study in Denmark. Genet Med. 2013;15(1):64–69. - PMC - PubMed

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The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Collaborators

Affiliations

The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical