Genetic susceptibility of ApoE to delirium and dementia in COVID-19 confirmed cases Project Summary Delirium is an acute confusional state that is commonly seen in hospitalized older adults during periods of infection, water and electrolyte imbalance or recovering from surgery. Delirium is often preventable, yet it appears to be particularly frequent and severe in the context of severe COVID-19 infection. Little is currently known of the mechanism linking COVID-19 to delirium, which is a risk factor for long-term cognitive impairment and dementia (mostly Alzheimer’s disease). We aim to study the genetic susceptibility of ApoE to COVID-19 related delirium and dementia as ApoE e4 allele has been associated with delirium and dementia using general population samples. In COVID-19 positive cases with no history of cognitive impairment and dementia, we hypothesize that patients with ApoE e3e4 or e4e4 genotypes are more likely than those with e3e3 (wild type) to experience delirium during COVID-19 related hospitalizations, and to be diagnosed with cognitive impairment and dementia in the 6 months following COVID-19 diagnosis. We also hypothesize that patients who develop delirium during coronavirus hospitalization are at higher risk of cognitive impairment and dementia in the 6-month follow-up. Additionally, COVID-19 is caused by the novel coronavirus SARS-Cov-2 that enters cells by targeting ACE2 receptors. We therefore also hypothesize that the associations between ApoE genotypes and delirium or dementia are moderated by genetic variants in the ACE2 gene. We propose to test the hypotheses using the UK Biobank data, including existing genetic and phenotypic data, now linked to COVID-19 testing results and related hospital admission and primary care data: 669 positive cases of 1,474 tested participants in the first month, with numbers growing substantially over time. The findings of this project will shed light on the biological mechanisms of delirium and dementia related to COVID-19, and have important implications for the management of public health and clinical interventions. This supplement grant is proposed under a NIA-funded R21 (R21AG060018) to study the role of ApoE e2 allele in aging via a wide range of aging phenotypes. The applicant group have extensive experience undertaking aging oriented analyses in UK Biobank, including papers on delirium and ApoE. Additionally, Pilling (Co-I) has a grant funded by the NIA-funded NIDUS Network (R24AG054259), to study genetic variation and predisposition to delirium.