Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.

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Gorijala, Priyanka 
Aslam, M Muaaz 
Dang, Lam-Ha T 
Xicota, L 
Fernandez, Maria V 

INTRODUCTION: 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. METHODS: AD polygenic risk scores (PRS) were tested for association with DS-related traits. RESULTS: 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, PRSAPOE , p = 2.84 × 10-4 ; PRS excluding APOE, PRSnonAPOE , p = 1.60 × 10-2 ). PRSAPOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS. DISCUSSION: 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. HIGHLIGHTS: 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.


Funder: NeuroGenomics and Informatics Center

Funder: Washington University School of Medicine

Funder: Chan Zuckerberg Initiative; doi:

Funder: Washington University

Funder: National Institute on Aging; doi:

Funder: German Center for Neurodegenerative Diseases; doi:

Funder: FLENI

Funder: Japan Agency for Medical Research and Development; doi:

Funder: KHIDI; doi:

Funder: National Institute of Biomedical Imaging and Bioengineering; doi:

Funder: NICHD; doi:

Dominantly Inherited Alzheimer Network, Down syndrome, PSEN1, PSEN2, amyloid precursor protein, apoliprotein E APOE, area under the curve, cerebrospinal fluid biomarkers, cognitive batteries, early-onset Alzheimer's disease, early-onset autosomal dominant, genetic architecture, genetic risk factor, late-onset Alzheimer's disease, polygenic risk score, sporadic late-onset Alzheimer's disease
Journal Title
Alzheimers Dement
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National Institutes of Health (U01 AG024904, P01AG003991, RF1AG053303, RF1AG058501, U01AG058922, RF1AG074007, R01AG064877)
Michael J. Fox Foundation (LI‐W81XWH2010849)
Alzheimer's Association Zenith (ZEN‐22‐848604)
JCM (P01AG03991)
Dominantly Inherited Alzheimer Network (U19AG032438)
Alzheimer's Association (SG‐20‐690363‐DIAN)
ADNI (U01 AG024904, W81XWH‐12‐2‐0012)
National Institute for Child Health and Human Development (U01 AG051406, U01 AG051412, U19 AG068054)
The Alzheimer's Disease Research Centers (P50 AG008702, P30 AG062421, P50 AG16537, P50 AG005133, P50 AG005681, P30 AG062715, P30 AG066519)
Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers (U54 HD090256, U54 HD087011, P50 HD105353)
National Center for Advancing Translational Sciences (UL1 TR001873, UL1 TR002373, UL1 TR001414, UL1 TR001857, UL1 TR002345)
Alzheimer's Disease and Related Dementias (U24 AG21886)