key: cord-0838099-vrqhu58w
authors: Tahira, Ana C.; Verjovski‐Almeida, Sergio; Ferreira, Sergio T.
title: Dementia is an age‐independent risk factor for severity and death in COVID‐19 inpatients
date: 2021-04-21
journal: Alzheimers Dement
DOI: 10.1002/alz.12352
sha: 3e2c68e0bf16d40fe91ee04af3370c8de64fca31
doc_id: 838099
cord_uid: vrqhu58w

INTRODUCTION: Dementia has been associated with COVID‐19 prevalence, but whether this reflects higher infection, older age of patients, or disease severity remains unclear. METHODS: We investigated a cohort of 12,863 UK Biobank community‐dwelling individuals > 65 years old (1814 individuals ≥ 80 years old) tested for COVID‐19. Individuals were stratified by age to account for age as a confounder. Risk factors were analyzed for COVID‐19–positive diagnosis, hospitalization, and death. RESULTS: All‐cause dementia, Alzheimer's disease (AD), and Parkinson's disease (PD) were associated with COVID‐19‐positive diagnosis, and all‐cause dementia and AD remained associated in individuals ≥ 80 years old. All‐cause dementia, AD, or PD were not risk factors for overall hospitalization, but increased the risk of hospitalization of COVID‐19 patients. All‐cause dementia and AD increased the risk of COVID‐19–related death, and all‐cause dementia was uniquely associated with increased death in ≥ 80‐year‐old patients. DISCUSSION: All‐cause dementia and AD are age‐independent risk factors for disease severity and death in COVID‐19.

Moreover, age is the major risk factor for development of dementia (notably Alzheimer's disease [AD] ), raising the possibility that the association between COVID-19 and all-cause dementia or AD might be explained by dementia patients being older on average than patients without dementia. Finally, it is still unclear whether AD and Parkinson's disease (PD), the two most prevalent neurodegenerative disorders in the elderly, are specifically associated with COVID-19 infection or its outcomes, or whether the association between COVID-19 and all-cause dementia results from contributions from other forms of dementia (non-AD, non-PD).

To address these questions, we investigated the prevalence of COVID-19 in a community-living cohort from the UK Biobank (UKB).

An advantage of using data from the UKB is that detailed clinical data 

We accessed the UKB database under application ID 64777. The UKB is a large prospective cohort comprising extensive phenotypic and genotypic data from approximately 500,000 individuals in the UK. 8 International Classification of Diseases (ICD) versions 9 and 10 (ICD As of March 29, 2020, testing capacity was increased to include swab testing for the wider population, which included asymptomatic people.

Test samples were recorded in UKB as being from a hospitalized inpatient if marked as originating from an acute (emergency) care provider, an Accident & Emergency department, an inpatient location, or from health care-associated infection; some individuals may not have been hospitalized after being seen at emergency facilities. Tests marked as being from "Healthcare Worker Testing" were not recorded as inpatient samples.

We used data on hospitalization (n = 932 COVID-19-positive hospitalized patients) as a proxy of disease severity, by consolidating hospitalization information from two UKB registries, namely "covid19_result.txt" and hospital episodes statistics (HES) "hesin.txt."

For hospital inpatient data records, the admission date was March 16, 2020 or later. Deaths registered in UKB with diagnosis "U07.1″ as primary or secondary cause were considered positive cases of death caused by COVID-19 (n = 397). To control for a possible bias associated with younger individuals experiencing milder (or no) symptoms after infection and never getting tested, we excluded younger individuals (aged 49-65) from the analyses, and only included individuals 66 years old and older tested for COVID-19. When age stratification was performed, we considered three groups, one aged between 66 and 74 years (n = 6182), another aged between 75 and 79 years (n = 4867), and a third aged between 80 and 86 years (n = 1814). Binary logistic regression was also performed using a multivariable model stepwise regression strategy with the stepAIC function of the MASS package from R. 12 In the multivariable stepwise regression, results are only shown for variables that composed the full model with the lowest Akaike information criterion (AIC) score. The AIC allows testing how well a model fits the data set without overfitting it: the model with the lowest AIC score is expected to strike an optimal balance between its ability to fit the data set while at the same time avoiding overfitting. When dementia was analyzed together with AD and PD in a multivariable stepwise regression model, we excluded AD and PD individuals from the "all-cause dementia" dataset and created an "Other dementia" group with the remaining individuals to have only independent variables in the model.

To investigate the impact of sociodemographic characteristics and clinical comorbidities on the diagnosis of COVID-19, we analyzed the entire cohort of tested individuals > 65 years old (n = 12,863), comprising 1167 COVID-19-positive and 11,696 negative individuals. This initial analysis showed that age, male sex, African ethnicity, BMI, high blood pressure, diabetes, angina, stroke, all-cause dementia, AD, and PD were associated with a higher risk of COVID-19 diagnosis, while asthma and cancer were inversely associated with risk of COVID-19 diagnosis (Table 1; Figure 1A ). Several of these risk factors remained significant in a multivariable stepwise regression model, notably age 

Age is the main risk factor for AD, and is also a risk factor for PD. Indeed, we confirmed that all groups of individuals with dementia (all-cause dementia, AD, and PD) in our cohort were on average older than nondemented individuals ( Figure S2 Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; OR, odds ratio.

and AD remained associated with a higher risk of positive diagnosis of COVID-19 in all age groups, while PD was a risk factor only in the two younger age groups ( Table 2 ). It is noteworthy that, among all comorbidities examined, only all-cause dementia (OR = 5.837, CI = 3.386-9.880, P < .001) and AD (OR = 6.551, CI = 2.892-14.398, P < .001) were associated with higher risk of COVID-19positive diagnosis in the elderly group (80 years old and older; Table 2 ).

To identify factors associated with higher risk of hospitalization (a proxy for disease severity), we analyzed the cohort of 12,863 tested individuals according to a univariable model using hospitalization as dependent variable. Within this cohort, 6232 individuals were hospitalized and 6631 were not hospitalized between March 16 and August 24, 2020. This analysis showed that age, male sex, BMI, and chronic disorders, including high blood pressure, diabetes, cancer, and cardiovascular diseases, were associated with higher overall risk of hospitalization ( Figure 1B , Table 3 ). However, no association with overall hospitalization was observed for all-cause dementia, AD, or PD. Similar results were obtained in a stepwise multivariable analysis (Table S3 in supporting information).

In contrast, all-cause dementia (OR (Table 3 ). In stepwise multivariable analysis, AD, PD, and other forms of dementia remained associated with higher risk of hospitalization due to COVID-19, together with age, male sex, African, Asian, other ethnicities, and BMI (Table S4 in supporting information). No interaction between age and all-cause dementia, AD, or PD was observed in multivariable interaction models for risk of hospitalization in the COVID-19-positive cohort.

Univariable analysis of the hospitalized cohort stratified by age into the three age groups described above showed that all-cause dementia was associated with higher risk of hospitalization of COVID-19positive inpatients in all three age groups, while AD was associated with the two older groups and PD was only associated with the intermediate age group (Table S5 in Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; OR, odds ratio.

were all-cause dementia and AD (Table S5 ). These findings point to allcause dementia as a risk factor for severe outcomes in elderly patients infected with COVID-19.

To determine risk factors associated with COVID-19-related death, we first performed a univariable analysis using death as dependent variable for the entire cohort of tested individuals (n = 12,863; 976 deaths).

As expected, age, male sex, and several clinical variables, including BMI, diabetes, cardiovascular diseases, high blood pressure, all-cause dementia, AD, and PD, were associated with higher overall risk of death ( Figure 1C ; Table 4 ). Interestingly, however, when risk of death specifically due to COVID-19 was analyzed, several variables, notably age, ceased to be associated, whereas all-cause dementia (OR = 2.172, CI = 1.231-3.900, P = .008) and AD (OR = 2.766, CI = 1.123-7.420, P = .032) remained associated with higher risk of COVID-19-related death ( Figure 1C ; Table 4 ).

In addition, in stepwise multivariable analysis, AD (OR = 2.814, CI = 1.095-7.233, P = .032) was associated with higher risk of death of COVID-19-positive inpatients, together with African ethnicity, while cancer events were associated with lower risk (Table S6 in supporting information). No significant interactions were observed between age and all-cause dementia, AD, or PD. Analysis in age-stratified groups showed that all-cause dementia remained specifically associated with COVID-19-related death in the oldest group (80 years old and older) in univariable analysis (Table S7 in supporting information). These findings indicate that all-cause dementia is a specific risk factor for death in COVID-19 patients, especially in the older (80 years old and older) population.

With approximately 80 million individuals infected globally, the COVID-19 pandemic is now in its second wave, with nearly half a million new cases daily worldwide. Although the number of cases in younger individuals appears to be increasing, older people are at higher risk of severe complications and poor outcomes of the disease, and Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; OR, odds ratio.

the number of COVID-19-related deaths is disproportionately high in the elderly. 3 In particular, residents in senior homes and in long-term care/nursing facilities have been severely impacted by COVID-19, with high rates of infection and death. 6, 7 COVID-19 has been associated with neurological complications, with manifestations ranging from headaches and anosmia to strokes and confusion, 13 and the possibility of long-term cognitive impairment in COVID-19 patients has been raised. 14 Remarkably, whereas several factors were found to be associated with increased overall risk of death in the studied cohort, only few variables, including all-cause dementia (and AD in particular), were found to be specifically associated with higher risk of COVID-19-related death. Of note, we further found that all-cause dementia remained significantly associated with increased death risk in the oldest (80 years old and older) individuals positive for SARS-CoV-2.

While BMI was found to be a significant disease risk factor in our cohort of COVID-19-tested individuals, the odds ratio for this 24 The same study found the presence of SARS-CoV-2 in the brainstem, which comprises the primary cardiovascular and respiratory control center, raising the possibility that CNS infection may mediate or aggravate respiratory/cardiovascular problems in COVID-19 patients. Patients with dementia (notably, AD) exhibit a chronic state of hyperactivation of the brain innate immunity 25 and may also present alterations in blood-brain barrier permeability (another possible pathway of CNS infection by SARS-CoV-2), suggesting a possible link between all-cause dementia and vulnerability in COVID-19. Finally, because dementia is a known risk factor for delirium in hospitalized older patients, 26 we examined the possibility that an increased prevalence of delirium in COVID-19 patients with dementia might underlie increased hospitalization or death. However, no association was found between delirium episodes and COVID-19positive diagnosis, hospitalization, or deaths in the studied cohort.

In conclusion, our findings highlight the prominent role of all-cause dementia, and in particular AD, over correlated risk factors for disease severity and death in COVID-19 patients, providing a target for early intervention. Genome-wide analyses of individuals in the UKB may reveal some of the molecular players leading to increased risk in patients with all-cause dementia, as recently reported for the apolipoprotein E ε4 allele. 27 While shielding these patients from infection may prove challenging due to their inherent need of caregivers and difficulty in adhering to strict personal health-care measures, these results suggest that patients with all-cause dementia should receive special attention upon hospitalization to prevent evolution of the disease to a potentially irreversible condition. The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

UKB received ethical approval from the North West Multi-centre

Research Ethics Committee (REC reference: 16/NW/0274). All participants gave written informed consent before enrolment in the study, which was conducted in accordance with the principles of the Declaration of Helsinki. Direct dissemination of the results to participants is not possible/applicable. This study was performed under UKB application number 64777.

STF conceived the work; SVA and STF obtained funding; ACT performed the statistical analyses; ACT and SVA verified the underlying data; ACT, SVA, and STF interpreted the results; ACT and STF wrote the original draft; ACT, SVA, and STF revised the manuscript and approved the final version.

UKB data used in the present work can be requested by bona fide researchers for approved projects, through https://www.ukbiobank.ac.

uk/

Modifiable and nonmodifiable risk factors for COVID-19, and comparison to risk factors for influenza and pneumonia: results from a UK Biobank prospective cohort study

Factors associated with COVID-19-related death using OpenSAFELY

Tackling challenges in care of Alzheimer's disease and other dementias amid the COVID-19 pandemic, now and in the future

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study

Epidemiology of Covid-19 in a long-term care facility in king County, Washington

Risk factors associated with mortality among residents with Coronavirus Disease 2019 (COVID-19) in long-term care facilities in Ontario, Canada

The UK Biobank resource with deep phenotyping and genomic data

NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimer's Dement

Mapping ICD-10 and ICD-10-CM codes to phecodes: workflow development and initial evaluation

The R Project for Statistical Computing. R_Core_Team

Modern Applied Statistics with S

Effects of COVID-19 on the nervous system

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the central nervous system

Preexisting comorbidities predicting COVID-19 and mortality in the UK biobank community cohort

Cognitive disorders associated with hospitalization of COVID-19: results from an observational cohort study

Comorbidities associated with mortality in 31,461 adults with COVID-19 in the United States: a federated electronic medical record analysis

COVID-19 and dementia: analyses of risk, disparity, and outcomes from electronic health records in the US. Alzheimer's Dement

Obesity and impaired metabolic health in patients with COVID-19

Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care organization

Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform

Clinical characteristics of patients who died of coronavirus disease 2019 in China

Comparison of sociodemographic and health-related characteristics of UK biobank participants with those of the general population

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

Innate immunity and neurodegeneration

Risk factors for incident delirium among older people in acute hospital medical units: a systematic review and meta-analysis

ApoE e4e4 genotype and mortality with COVID-19 in UK Biobank

SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article