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

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

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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).

Original language	English
Article number	105433
Journal	EBioMedicine
Volume	110
DOIs	https://doi.org/10.1016/j.ebiom.2024.105433
State	Published - Dec 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

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).The Alzheimer's Biomarkers Consortium–Down Syndrome (ABC-DS) is funded by the National Institute on Aging and the National Institute of Child Health and Human Development (U01 AG051406, U01 AG051412, U19 AG068054). In addition, the work contained in this publication was also supported through the additional National Institutes of Health supports: R01 AG014673, P01 HD035897, U54 HD079123, and R56 AG061837; The Alzheimer's Disease Research Centers Program (P50 AG008702, P30 AG062421, P50 AG16537, P50 AG005133, P50 AG005681, P30 AG062715, and P30 AG066519); the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program (U54 HD090256, U54 HD087011, and P50 HD105353); the National Center for Advancing Translational Sciences (UL1 TR001873, UL1 TR002373, UL1 TR001414, UL1 TR001857, Disease and Related Dementias (U24 AG21886); and DS-Connect® (The Down Syndrome Registry) supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and by NYS through its Office for People with Developmental Disabilities. In Cambridge, UK this research was supported by the NIHR Cambridge Biomedical Research Centre and the Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge, UK. The authors are grateful to the ABC-DS and the legacy study participants, their families and care providers, and the ABC-DS and the legacy research and support staff for their contributions to this study. This manuscript has been reviewed by ABC-DS investigators for scientific content and consistency of data interpretation with previous ABC-DS study publications. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the CPFT, the NIHR or the UK Department of Health and Social Care. The Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) is funded by the National Institute on Aging and the National Institute for Child Health and Human Development (U01 AG051406, U01 AG051412, U19 AG068054). In addition, the work contained in this publication was also supported through the additional National Institutes of Health supports: R01 AG014673, P01 HD035897, U54 HD079123, and R56 AG061837; The Alzheimer’s Disease Research Centers Program (P50 AG008702, P30 AG062421, P50 AG16537, P50 AG005133, P50 AG005681, P30 AG062715, and P30 AG066519); the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program (U54 HD090256, U54 HD087011, and P50 HD105353); the National Center for Advancing Translational Sciences (UL1 TR001873, UL1 TR002373, UL1 TR001414, UL1 TR001857, Disease and Related Dementias (U24 AG21886); and DS-Connect® (The Down Syndrome Registry) supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and by NYS through its Office for People with Developmental Disabilities. In Cambridge, UK this research was supported by the NIHR Cambridge Biomedical Research Centre and the Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge, UK. 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.

Funders	Funder number
National Institute on Handicapped Research
Eunice Kennedy Shriver National Institute of Child Health and Human Development
NYS Bureau of Vital Records
Roche Italia
National Institutes of Health (NIH)
Windsor Research Unit
1Florida Alzheimer's Disease Research Center
Fulbourn Hospital
UK Department of Health and Social Care
NIHR Cambridge Biomedical Research Centre
Fundação Universitaria do ABC, Faculdade de Medicina do ABC
Autism Speaks Inc
CPFT
National Institute on Aging
Down Syndrome Registry
National Centralized Repository for Alzheimer's Disease and Related Dementias	U24 AG21886
National Center for Advancing Translational Sciences (NCATS)	UL1 TR002373, UL1 TR001873, UL1 TR001414, UL1 TR001857
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research	P50 AG008702, P01 HD035897, P30 AG062421, U54 HD087011, P50 AG005681, P50 HD105353, U19 AG068054, P50 AG005133, R01 AG014673, P30 AG062715, P30 AG066519, R56 AG061837, U01 AG051412, U01 AG051406, P50 AG16537, U54 HD090256, U54 HD079123
Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program	U54 HD090256, U54 HD087011, P50 HD105353

Keywords

Alzheimer's disease
CSF
Down syndrome
Mosaicism
PET
Plasma biomarkers

ASJC Scopus subject areas

General Medicine
General Biochemistry, Genetics and Molecular Biology

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10.1016/j.ebiom.2024.105433

Cite this

@article{fe31a8892fb4463ea13e7e5d1b762a24,

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

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",

author = "Laura Xicota and Dang, \{Lam Ha T.\} and Alice Lee and Sharon Krinsky-McHale and Deborah Pang and Lisa Melilli and Sid O'Bryant and Henson, \{Rachel L.\} and Charles Laymon and Florence Lai and Rosas, \{H. Diana\} and Ances, \{Beau M.\} and Ira Lott and Christy Hom and Bradley Christian and Sigan Hartley and Shahid Zaman and Elizabeth Head and Mark Mapstone and Zhezhen Jin and Wayne Silverman and Nicole Schupf and Benjamin Handen and Lee, \{Joseph H.\} and Aizenstein, \{Howard J.\} and Andrews, \{Howard F.\} and Karen Bell and Rasmus Birn and Brickman, \{Adam M.\} and Peter Bulova and Amrita Cheema and Kewei Chen and Christian, \{Bradley T.\} and Isabel Clare and Lorraine Clark and Cohen, \{Ann D.\} and Constantino, \{John N.\} and Doran, \{Eric W.\} and Anne Fagan and Eleanor Feingold and Foroud, \{Tatiana M.\} and Handen, \{Benjamin L.\} and Jordan Harp and Hartley, \{Sigan L.\} and Rachel Henson and Lawrence Honig and Ikonomovic, \{Milos D.\} and Johnson, \{Sterling C.\} and Courtney Jordan and Frederick Schmitt",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = dec,

doi = "10.1016/j.ebiom.2024.105433",

language = "English",

volume = "110",

}

TY - JOUR

T1 - The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

AU - Xicota, Laura

AU - Dang, Lam Ha T.

AU - Lee, Alice

AU - Krinsky-McHale, Sharon

AU - Pang, Deborah

AU - Melilli, Lisa

AU - O'Bryant, Sid

AU - Henson, Rachel L.

AU - Laymon, Charles

AU - Lai, Florence

AU - Rosas, H. Diana

AU - Ances, Beau M.

AU - Lott, Ira

AU - Hom, Christy

AU - Christian, Bradley

AU - Hartley, Sigan

AU - Zaman, Shahid

AU - Head, Elizabeth

AU - Mapstone, Mark

AU - Jin, Zhezhen

AU - Silverman, Wayne

AU - Schupf, Nicole

AU - Handen, Benjamin

AU - Lee, Joseph H.

AU - Aizenstein, Howard J.

AU - Andrews, Howard F.

AU - Bell, Karen

AU - Birn, Rasmus

AU - Brickman, Adam M.

AU - Bulova, Peter

AU - Cheema, Amrita

AU - Chen, Kewei

AU - Christian, Bradley T.

AU - Clare, Isabel

AU - Clark, Lorraine

AU - Cohen, Ann D.

AU - Constantino, John N.

AU - Doran, Eric W.

AU - Fagan, Anne

AU - Feingold, Eleanor

AU - Foroud, Tatiana M.

AU - Handen, Benjamin L.

AU - Harp, Jordan

AU - Hartley, Sigan L.

AU - Henson, Rachel

AU - Honig, Lawrence

AU - Ikonomovic, Milos D.

AU - Johnson, Sterling C.

AU - Jordan, Courtney

AU - Schmitt, Frederick

PY - 2024/12

Y1 - 2024/12

N2 - 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).

AB - 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).

KW - Alzheimer's disease

KW - CSF

KW - Down syndrome

KW - Mosaicism

KW - PET

KW - Plasma biomarkers

UR - https://www.scopus.com/pages/publications/85208045919

UR - https://www.scopus.com/pages/publications/85208045919#tab=citedBy

U2 - 10.1016/j.ebiom.2024.105433

DO - 10.1016/j.ebiom.2024.105433

M3 - Article

C2 - 39500037

AN - SCOPUS:85208045919

VL - 110

JO - EBioMedicine

JF - EBioMedicine

M1 - 105433

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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