key: cord-0972629-5npvq577
authors: Kuo, Chia-Ling; Pilling, Luke C; Atkins, Janice L; Fortinsky, Richard H; Kuchel, George A; Melzer, David
title: APOE e4 genotypes increase risk of delirium during COVID-19 related hospitalizations: evidence from a large United Kingdom cohort
date: 2021-06-25
journal: J Gerontol A Biol Sci Med Sci
DOI: 10.1093/gerona/glab184
sha: 335600f422e72ea5ae4924b67d763cce8d200521
doc_id: 972629
cord_uid: 5npvq577

nan

A c c e p t e d M a n u s c r i p t Delirium is an acute confusional state, and is reported to be particularly frequent and severe in older adults with severe COVID-19 infection [1] . Little is currently known of the mechanisms linking COVID-19 to delirium. Given that the APOE e4 allele has been associated with delirium [2] and risk of having severe COVID-19 [3, 4] in the general population, we hypothesized that the APOE e4 allele may be associated with increased risk of delirium during COVID-19 related hospitalizations.

To test the hypothesis, we used data from European-ancestry participants of the UK Biobank, F05.9) were restricted to those in the Acute Phase (AP delirium; within 30 days after test-confirmed COVID-19) [5] . Those diagnosed after 30 days (long COVID) were too few to analyze. Fine-and-Gray competing risk models accounting for the competing risk of mortality were used, adjusting for age, sex, and the top five genetic principal components from the European-ancestry participants. In the e4-delirium association analysis, 1,363 participants were hospitalized after test-confirmed COVID-19, of whom 358 were e3e4s (n=49 delirium cases, 43 AP), 64 were e4e4s (n=14, 13 AP), and 941 were e3e3s (n=66, 52 AP). e3e4 and e4e4 genotypes accounted for 47% (56/118) of AP delirium cases from all hospitalized after test-confirmed COVID-19 (n=1,575), and 52% (56/108) of AP delirium cases from those restricted to e3e4s, e4e4s, and e3e3s only. Both e3e4s (HR e3e4 =2.29, 95% CI: 1.54-3.41, p=4.8010 -5 ) and e4e4s (HR e4e4 =4.94, 95% CI: 2.69-9.09, p=2.8010 -7 ) were at higher risk of AP delirium compared to e3e3s. For sensitivity analysis, we used only those with a COVID diagnosis during hospitalization. We also analyzed hospitalized patients excluding those with pre-existing dementia before the first COVID positive date, and excluding one in third-degree or closer pairs, and the results were consistent in all analyses (Table 1) .

For exploratory purposes, the associations between e4 genotypes and dementia are well established [6] , and could possibly hold in patients with test-confirmed COVID-19. Currently, most of new dementia cases after test-confirmed COVID-19 were recorded in the AP (39 of 55 in e3e4, e4e4, or e3e3 genotypes). While we found that e4 genotypes were associated with increased risk of AP dementia (HR e3e4 =2.24, 95% CI: 1.13-4.44, p=0.02; HR e4e4 =7.86, 95% CI: 3.06-20.18, p=1.810 -5 ), some of these patients likely developed dementia before COVID-19 infection, which was not captured in the hospital admission records until COVID-19 related hospitalizations. When more post COVID dementia cases are diagnosed, using additional primary care data would help exclude those with preexisting dementia and a wash-out period may be set to confirm incident cases.

To conclude, we previously showed that APOE e4 genotypes are associated with increased COVID-19 severity [3, 4] . In this letter, we add that delirium is enriched in e4 genotypes after test-confirmed COVID-19. Inevitably, our study has limitations: included samples restricted to white, hospitalized COVID-19 patients; no proper COVID-free controls to compare with for e4-delirium associations; limited data at the pandemic to characterize the samples and to test robustness of the associations. Our findings provide early evidence and need to be confirmed by independent replication in larger samples. Future investigations are needed to understand the underlying mechanisms and to study those not severely infected or hospitalized for long-term health impact from COVID-19 infection. 

Delirium in Older Patients with COVID-19 Presenting to the Emergency Department

Low Vitamin D Levels and Risk of Incident Delirium in 351,000 Older UK Biobank Participants

ApoE e4e4 Genotype and Mortality with COVID-19 in UK Biobank

APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort

Long COVID guidelines need to reflect lived experience

Delirium in older adults is associated with development of new dementia: a systematic review and meta-analysis

M a n u s c r i p t A c c e p t e d M a n u s c r i p t Hazard ratio comparing e3e4s to e3e3s (HR e3e4 ) and that comparing e4e4s to e3e3s (HR e4e4 ) from Fine-and-Gray competing risk models accounting for the competing risk of mortality, adjusting for age, sex, and the top five genetic principal components from the European-ancestry participants in the UK Biobank