Genome‐wide association analyses identify candidate loci for amyloid imaging and plasma biomarkers in adults with Down syndrome
Year: 2025
Type: review
Study design: Observational Study
Abstract: BACKGROUND: People with Down syndrome (DS) overproduce amyloid-beta (Aβ) due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and consequently accumulate brain amyloid load at younger ages. We conducted genome-wide association (GWA) analyses on amyloid imaging and plasma biomarkers to discern the genetic architecture of amyloid burden in DS. METHODS: GWA analyses were performed on amyloid positron emission tomography (PET) and plasma biomarkers (Aβ40, Aβ42, Aβ42/40 ratio) in participants from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) and on plasma Aβ biomarkers available in an independent DS cohort, followed by meta-analysis of plasma Aβ biomarker data. RESULTS: Meta-analysis on plasma biomarkers identified four novel loci: two for Aβ42 (PFKFB3/rs147647642, p = 2.83E-08; DLX3-PICART1/rs12952028, p = 9.31E-09) and two for Aβ40 (LINC01941-GYPC/rs78338676, p = 9.33E-09; PDE4D/rs146261781, p = 9.97E-08). Five genome-wide signals were observed for amyloid-PET in the ABC-DS cohort that need confirmation in an independent DS dataset. DISCUSSION: Despite the small sample, our findings highlight the unique genetic architecture of amyloid burden in DS. HIGHLIGHTS: Genetic markers for amyloid biomarkers in Down syndrome (DS) were identified. Meta-analyses identified four novel loci for plasma amyloid in two DS cohorts. Five loci associated with amyloid positron emission tomography levels were identified in the Alzheimer's Biomarker Consortium-Down Syndrome cohort. Multi-trait analysis revealed loci linking variants to amyloid biomarkers.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.70358
Authors: M. Muaaz Aslam, Lam‐Ha T. Dang, Ruyu Shi, Kang‐Hsien Fan, Asma Naseer Cheema, Laura Xicota, Danveet Minhas, Weiquan Luo, Narges Zafari, Vibha Acharya, Eleanor Feingold, Sharon Krinsky‐McHale, Charles M. Laymon, Ann Cohen, Benjamin L. Handen, Bradley T. Christian, Elizabeth Head, Mark E. Mapstone, Joseph H. Lee, Carlos Cruchaga, M. Ilyas Kamboh
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Awards: Genetic Architecture of Alzheimer’s disease Proteinopathies, G1369195717, G1661677298, G2142974134, G2640555407, Waisman Intellectual and Developmental Disabilities Research Center, Alzheimer's Disease Research Center, Aging and Dementia in Adults with Down Syndrome, G3483586962, Institute for Clinical and Translational Science, G3818147302, Neurodegeneration in Aging Down Syndrome (NiAD): A Longitudinal Study of Cognition and Biomarkers of Alzheimer's Disease, Identification of protective factors for cognitive resilience in adults with Down Syndrome: A multi-omic study, Epidemiology of menopause and dementia in Down syndrome, G499514328, Biomarkers of Alzheimer's Disease in Adults with Down Syndrome, WASHINGTON UNIVERSITY INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER, G5459524459, Alzheimer's Disease Research Center - Overall, Alzheimer's Disease Research Center, G75188610, G873702183, G9000000175, G9000061259, G9000070217, G9000126115, G9000134521, G9000198685, G9000239813, G9000257646, G9000354213, Clinical and Translational Science Award, University of Pittsburgh Clinical and Translational Science Institute, University of Wisconsin Institute for Clinical and Translational Research, Waisman Center Intellectual and Developmental Disabilities Research Center, Alzheimer Biomarker Consortium - Down Syndrome (ABC-DS), Alzheimer's Disease Research Center, Washington University Institute of Clinical and Translational Sciences, Wisconsin Alzheimer's Disease Research Center, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), Massachusetts Alzheimer's Disease Research Center (MADRC), The Alzheimer's Disease Research Center at the University of California, Irvine
OpenAlex ID: W4412487053