Understanding the role of ApoE2 in longevity and age-related diseases and conditions using 500,000 UK Biobank participants

Genetic susceptibility of ApoE to delirium and dementia in COVID-19confirmed casesProject Summary: Delirium is an acute confusional state that is commonly seen in hospitalized older adultsduring 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 thecontext of severe COVID-19 infection. Little is currently known of the mechanism linkingCOVID-19 to delirium, which is a risk factor for long-term cognitive impairment anddementia (mostly Alzheimer's disease). We aim to study the genetic susceptibility ofApoE to COVID-19 related delirium and dementia as ApoE e4 allele has beenassociated with delirium and dementia using general population samples. In COVID-19positive cases with no history of cognitive impairment and dementia, we hypothesizethat 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 bediagnosed with cognitive impairment and dementia in the 6 months following COVID-19diagnosis. We also hypothesize that patients who develop delirium during coronavirushospitalization are at higher risk of cognitive impairment and dementia in the 6-monthfollow-up. Additionally, COVID-19 is caused by the novel coronavirus SARS-Cov-2 thatenters cells by targeting ACE2 receptors. We therefore also hypothesize that theassociations between ApoE genotypes and delirium or dementia are moderated bygenetic variants in the ACE2 gene. We propose to test the hypotheses using the UKBiobank data, including existing genetic and phenotypic data, now linked to COVID-19testing results and related hospital admission and primary care data: 669 positive casesof 1,474 tested participants in the first month, with numbers growing substantially overtime. The findings of this project will shed light on the biological mechanisms of deliriumand dementia related to COVID-19, and have important implications for themanagement of public health and clinical interventions. This supplement grant isproposed under a NIA-funded R21 (R21AG060018) to study the role of ApoE e2 allelein aging via a wide range of aging phenotypes. The applicant group have extensiveexperience undertaking aging oriented analyses in UK Biobank, including papers ondelirium and ApoE. Additionally, Pilling (Co-I) has a grant funded by the NIA-fundedNIDUS Network (R24AG054259), to study genetic variation and predisposition todelirium.