biostudies-literatureGorijala PNational Center for Advancing Translational SciencesEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD NIH HHSNCATS NIH HHSNIBIB NIH HHSNIA NIH HHSNational Institutes of HealthAlzheimer&apos;s AssociationChan Zuckerberg InitiativeNational Institute on AgingDeutsches Zentrum für Neurodegenerative ErkrankungenJapan Agency for Medical Research and DevelopmentAlzheimer&apos;s Disease Neuroimaging InitiativeKorea Health Industry Development InstituteAlzheimer's AssociationNIH HHSNational Institute of Biomedical Imaging and BioengineeringMichael J. Fox Foundation for Parkinson&apos;s Research1038-1049https://www.ebi.ac.uk/biostudies/studies/S-EPMC10916941biostudies-literatureUnknown20(2)<h4>Introduction</h4>This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers.<h4>Methods</h4>AD polygenic risk scores (PRS) were tested for association with DS-related traits.<h4>Results</h4>The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRS_APOE , p = 2.84 × 10^-4 ; PRS excluding APOE, PRS_nonAPOE , p = 1.60 × 10^-2 ). PRS_APOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS.<h4>Discussion</h4>These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits.<h4>Highlights</h4>Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.Alzheimer's & dementia : the journal of the Alzheimer's AssociationAlzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.PMC10916941U01AG058922W81XWH‐12‐2‐0012RF1 AG044546RF1AG058501UL1 TR002373R01AG064877RF1 AG071706U54 HD087011SG‐20‐690363‐DIANP50 AG005681P30 AG066519P30 AG062715U24 AG021886U01 AG051412R01 AG044546RF1AG074007P30 AG066444R01 AG064877U01 AG058922R01 AG064614P50 AG008702LI‐W81XWH2010849UL1 TR001873UL1 TR002345P30 AG062421RF1 AG074007UL1 TR001414RF1AG053303U19 AG068054P50 HD105353P50 AG005133RF1 AG058501U19 AG032438UL1 TR001857RF1 AG053303U01 AG051406SG-20-690363-DIANP01AG003991U54 HD090256U01 AG024904P01 AG026276P01 AG003991Dominantly Inherited Alzheimer Network (DIAN), the Alzheimer's Disease Neuroimaging Initiative (ADNI)Xicota LChhatwal JPMapstone MHassenstab JFeingold EHom CLAnces BMFernandez MVZaman SHCruchaga CGorijala PHartley SLKamboh MIFan KHSurace EIAslam MMNIA-LOAD family study, for the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) InvestigatorsDang LTPerrin RJSung YJLee JHfalseAlzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.<h4>Introduction</h4>This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers.<h4>Methods</h4>AD polygenic risk scores (PRS) were tested for association with DS-related traits.<h4>Results</h4>The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRS_APOE , p = 2.84 × 10^-4 ; PRS excluding APOE, PRS_nonAPOE , p = 1.60 × 10^-2 ). PRS_APOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS.<h4>Discussion</h4>These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits.<h4>Highlights</h4>Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.2024-01-01T00:00:00Z2024 Feb2025-08-12T03:04:38.886Z2025-08-12T03:04:38.886ZS-EPMC109169413785544710.1002/alz.13506