TY - JOUR
T1 - The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome
AU - Alzheimer’s Biomarker Consortium –Down Syndrome (ABC-DS)
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
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 - Ances, Beau M.
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 - Kamboh, M. Ilyas
AU - Keator, David
AU - Klunk, William E.
AU - Kofler, Julia K.
AU - Kreisl, William Charles
AU - Krinsky-McHale, Sharon J.
AU - Lao, Patrick
AU - Lott, Ira T.
AU - Lupson, Victoria
AU - Mathis, Chester A.
AU - Minhas, Davneet Singh
AU - Nadkarni, Neelesh
AU - O'Bryant, Sid
AU - Parisi, Melisa
AU - Pettersen, Melissa
AU - Price, Julie C.
AU - Pulsifer, Margaret
AU - Rafii, Michael S.
AU - Reiman, Eric
AU - Rizvi, Batool
AU - Ryan, Laurie
AU - Schmitt, Frederick
AU - Silverman, Wayne P.
AU - Tudorascu, Dana L.
AU - Tumuluru, Rameshwari
AU - Tycko, Benjamin
AU - Varadarajan, Badri
AU - White, Desiree A.
AU - Yassa, Michael A.
AU - Zhang, Fan
N1 - Publisher Copyright:
© 2024 The Author(s)
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 - http://www.scopus.com/inward/record.url?scp=85208045919&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2024.105433
DO - 10.1016/j.ebiom.2024.105433
M3 - Article
C2 - 39500037
AN - SCOPUS:85208045919
SN - 2352-3964
VL - 110
JO - EBioMedicine
JF - EBioMedicine
M1 - 105433
ER -