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Underlying pleiotropic connections between Alzheimer's Disease and its comorbidities may contribute

Anni Moore, BS, Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA Marlyn D. Ritchie, PhD, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Poster # 24

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, with one in nine people over the age of 65 living with disease in 2023. Despite its prevalence, no effective treatment or single etiologic driver of AD has been discovered. Over 50% of AD cases are brought on by a combination of small-effect common genetic variants, implicated in numerous pathway disruptions that exacerbate each other to promote disease. One strategy to gain insight into AD progression is to investigate shared pleiotropy between AD and other highly co-occurring diseases to uncover overlapping mechanisms. Here we used the results of a phenome wide association study (PheWAS) to find associations between previously associated AD variants with electronic health record (EHR) diseases from the UK Biobank (UKBB) from 361,194 individuals of European ancestry. With 633 phenotypes and 497 previously AD associated variants from the Alzheimer's Disease Variant Portal (ADVP), we found 81 significant associations (p<5*10-8), primarily in cardiac and immune related diseases. Chronic ischemic heart disease was most significantly associated, with 14 AD associated variants. Specifically within the major histocompatibility complex (MHC) region, 8 AD variants were significantly associated with intestinal malabsorption and 7 with ulcerative colitis. We will replicate these findings in the Penn Medicine Biobank (PMBB) (n=43,624 patients) and NIH's All of Us Biobank (n=245,000) which has yet to be used for investigation in the context of AD. Both biobanks contain genotype and EHR data for all individuals and have higher diverse patient ancestry than UKBB.

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