Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome
Priyanka Gorijala, Muhammad Aslam, Lam‐Ha T. Dang, Laura Xicota, María Victoria Fernández, Yun Ju Sung, Kang‐Hsien Fan, Eleanor Feingold, Ezequiel Surace, Jasmeer P. Chhatwal, Christy Hom, Dominantly Inherited Alzheimer Network (DIAN), the Alzheimer's Disease Neuroimaging Initiative (ADNI), Sigan L. Hartley, Jason Hassenstab, Richard J. Perrin, Mark Mapstone, Shahid Zaman, Beau M. Ances, M. Ilyas Kamboh, Joseph H. Lee, Carlos Cruchaga
Abstract
Abstract 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 , 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. 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.