key: cord-1042930-fu0e0sxj authors: Wang, Ying; Li, Mingfei; Kazis, Lewis E.; Xia, Weiming title: Clinical outcomes of COVID‐19 infection among patients with Alzheimer's disease or mild cognitive impairment date: 2022-04-04 journal: Alzheimers Dement DOI: 10.1002/alz.12665 sha: f9334205a6e50fd9593587fed651d972b61f4079 doc_id: 1042930 cord_uid: fu0e0sxj INTRODUCTION: Alzheimer's disease (AD) and COVID‐19 share common risk factors including hypertension. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are frequently prescribed antihypertension medications. METHODS: This study analyzed 436,823 veterans tested for SARS‐CoV‐2 infection. We conducted both classical and propensity score weighted logistic models to compare COVID‐19 outcomes between patients with AD or mild cognitive impairment (MCI) to those without cognitive impairment, and examined effect of ACEI/ARB prescription. RESULTS: There was a statistically significant association between AD and increased odds of infection and mortality. MCI was not found to be a risk factor for infection. Subjects with MCI exhibited poor clinical outcomes. Prescribing ARBs but not ACEIs was significantly associated with a lower risk of COVID‐19 occurrence among AD and MCI patients. DISCUSSION: Exploring beneficial effects of existing medications to reduce the impact of COVID‐19 on patients with AD or MCI is highly significant. HIGHLIGHTS: There is significant association between Alzheimer's disease (AD) and increased risk of COVID‐19 infection and odds of mortality. Subjects with mild cognitive impairment (MCI) defined by claims data exhibit poor clinical outcomes, but MCI was not found to be a risk factor for severe acute respiratory syndrome coronavirus 2 infection. Prescribing angiotensin II receptor blockers was significantly associated with a lower risk of COVID‐19 occurrence among AD/MCI patients. enzyme 2 (ACE2) receptor, which is expressed in various human organs. The expression of ACE2 was found in neurons and non-neuron cells (mainly astrocytes and oligodendrocytes) of the human brain. 15 Analysis of post mortem tissue showed that ACE2 expression is upregulated in the brain of AD patients compared to those from cognitively normal controls. 16 It is not clear whether patients with AD are more susceptible to COVID-19 infection due to an increase in ACE2 expression. Electronic health records (EHR) of 61.9 million subjects were analyzed to examine the associations between COVID-19 and different types of dementia. 17 Patients with dementia were at increased risk for COVID-19 infection, where AD demonstrated a strong association with an unadjusted odds ratio (OR) of 1.86. 17 In this study, we investigated the association of AD with the risk of COVID-19 infection with covariate adjustments for comorbidities and other sociodemographic factors. Previously, we and others reported the beneficial effects of long-term use of antihypertension medications on the time to occurrence of a diagnosis of AD, including angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) in a number of epidemiological studies. [18] [19] [20] [21] [22] [23] We further explore in this paper the associations of ARB and ACEI that are prescribed on the occurrence of COVID-19 among patients with AD or MCI. This retrospective case-control study included 436,823 adult patients national health-care system, including 5128 patients (1.2%) who were diagnosed with AD, and 431,695 non-AD subjects ( Table 1) . We The primary dependent variable for this study was COVID-19 infec- Sociodemographic characteristics and clinical characteristics of the patient were listed including the Charlson Comorbidity Index (CCI; Table 1 ). Body mass index (BMI) distribution within our cohort ( Figure S1 in supporting information) was divided into four categories: normal, overweight, obese, and extremely obese ( Table 1 ). The relevant comorbidities and risk factors were defined based on ICD-10 codes from the 2-year period preceding the index date. The BMI and the CCI were measured or created at the index date. The status of nursing home stay was collected to limit the influence of a known confounder, that is, patients with AD are less likely to continue practicing good personal hygiene and common prevention routines, such as wearing a facial mask, washing hands regularly, and maintaining social distancing protocols. Descriptive statistics were used to summarize the demographic and clinical characteristics of the patients. Continuous variables were described in terms of means and standard deviations (SDs), and categorical variables were summarized as counts and percentages. Due to the potential imbalance between AD versus non-AD groups and MCI versus non-MCI group on baseline covariates, we used propensity score weighting (PSW). This technique is commonly used in non-experimental studies to account for selection assignment differences between exposure and comparison groups. 25 The propensity score weights were estimated using demographic characteristics of the patients and their status of nursing home stay. We used the gradient boosting method (GBM) to compute a propensity score (PS) for each patient. Multivariate logistic regressions with and without PSW were used to analyze the association between AD/MCI and COVID-19 infection, and the association of the ACEI/ARB prescriptions with All analyses were adjusted for demographic and clinical characteristics, and the ORs were estimated with 95% confidence intervals (CI), for maximum likelihood method iterations (ML). A P-value of less than .05 is considered significant. In addition, we applied bootstrap method as the sensitivity analysis to estimate the CI of the regression coefficients and examine the robustness of our major results. We re-estimated the 95% bootstrapped CI of ORs from a simulation with 1000 samples. The bootstrapping procedure confirmed the stability of the results because it is asymptotically more accurate than the standard CIs obtained from sample variance and assumptions of normality. To further confirm the significant association of AD with those diagnosed with COVID-19, we performed a sensitivity analysis among the subcohort of patients not living in a nursing home. A total of 436,823 adult patients (≥ 50 years old and < 90 years old) were tested for COVID-19 during the study period, of whom 40,993 (9.38%) were positive. The majority (92.4%) of the study population were male, and our study population had a higher proportion of men than in the general population ( Among the 5010 AD patients, 176 patients had an ACEI prescription only and 685 patients had an ARB prescription only (Table 2) . Among the 685 patients who were prescribed ARB, long-term care facility patients made up 18.0%, and among the 1761 patients who were prescribed ACEI, 22.5% patients were in long-term care. We examined the distribution of our study population based on their COVID-19 positive/negative test results and their clinical severity levels ( Table 3) . We specifically analyzed the profiles of COVID-19positive AD (Table 4 ) and MCI patients (Table 4) Patients with AD were associated with higher odds than patients without AD of being diagnosed with COVID- 19 Figure 1 ). We did not observe a statistically significant association between AD and the use of ICU or mechanical ventilation (Table 5, Figure 1 ). Sensitivity analyses using bootstrapping for the CI of the ORs (Table S1A in supporting information) were comparable to our main findings (Table 5, Figure 1 ), supporting the robustness of the associations reported in our analyses. Because AD patients living in nursing homes could be a risk factor for COVID-19 infection, we extracted AD patients living outside of nursing homes and observed a similar, statistically F I G U R E 1 Odds ratios of association of Alzheimer's disease (AD) with COVID-19 infection and clinical outcomes. Odds with and without propensity score weighting of COVID-19 infection, hospitalization, use of intensive care unit (ICU) or mechanical ventilation, and mortality were illustrated in patients with AD compared to patients without AD, after adjusting for age at index date, race, sex, ethnicity, diabetes, pulmonary disease, kidney disease, coronary atherosclerotic heart disease, chronic liver disease, hyperlipidemia, cancer, smoking status, stroke, heart failure, alcohol dependency, drug dependency, body mass index, Charlson Comorbidity Index, and status of nursing home stay Table 6 ). When we examined the patients with MCI, we did not observe a signif- Figure 2 ). Sensitivity analyses using bootstrapping for the confidence intervals for logistic regression were comparable to our findings (Table S1A ), supporting the robustness of the associations reported in our analyses. Patients prescribed ARBs had a lower risk of a positive COVID-19 test outcome (OR = 0.657, 95% CI [0.501, 0.861], P-value = .002), compared to patients not prescribed ACEI or ARB. These results were confirmed with the logistic model with PSW (OR = 0.644, 95% CI [0.567, .731], P-value < .001; Table 8, Figure 3 ). However, prescription of ACEIs had no significant association with a positive COVID-19 test result. We further examined the association of medications prescribed on the clinical outcomes. Among AD patients who tested positive for COVID-19, neither ACEIs nor ARBs had a significant association with any of the severity levels (Table 8, Figure 3 ) in both the logistic and the PSW logistic models. to the reference group (no ACEI and no ARB; Table 9 , Figure 4 ). This result was confirmed with the PSW logistic model: the OR for ARB was 0.886 with 95% CI (0.827, 0.949) and P-value = .001 (Table 9, Figure 4) . To the best of our knowledge, this is one of the largest retrospective case-control studies evaluating the association of those diagnosed with AD/MCI and COVID-19 infection together with informa-tion on medication treatment and clinical outcomes. The association between AD and COVID-19 in our study is consistent with another large cohort study on dementia that leveraged 61.9 million EHRs. 17 However, important differences in the study design should be noted. Our results suggest a 69% increased odds of a COVID-19 infection among AD patients and beneficial effect of ARB prescription. The relationship between AD and mortality among COVID-19-positive patients revealed by this study has significant clinical implications. Next, the hospitalization and mortality status were evaluated using Mechanistically, our findings are consistent with the speculation that the increased BBB permeability renders patients with AD vulnerable to viral infections. [28] [29] [30] Prior studies have shown that BBB impairment is a stable characteristic of AD patients [31] [32] [33] [34] and suggested that many infectious agents in the CNS, including viruses, bacteria, and fungi, were associated with AD patients. 30, [35] [36] [37] [38] [39] [40] Our study has several limitations. First, there were substantial differences in terms of demographics, clinical characteristics, and the status of nursing home stay between AD/MCI versus non-AD/MCI patients, even though we attempted to limit the biases by balancing and adjusting these differences using multivariable regression with PSW. Second, the participants in our study took the COVID-19 test voluntarily. We did not account for the various social and behavioral reasons associated with the decision for COVID-19 testing. Several unmeasured variable factors, such as behavioral attitudes, sociodemographic disparities, and cultural attitudes may have contributed to this decision. Third, due to the overall nature of the population of veterans who had served in the US military, our study population had a higher proportion of males than the general population, and results are limited to males, predominantly White ( Table 1 ). The impact of the SARS-CoV-2 infection on AD and MCI patients is multifaceted, 41 and the effects on clinical outcomes of COVID-19 are heterogeneous in general, except for a specific increase in mortality. 42 We understand that our results may be statistically significant but not clinically important to change current practices. The sample size of this study is very high and the significance of results should be interpreted with caution. The effect size of our primary finding is larger than small effect size, 26 using the effect size as the approach is appropriate and conveys the clinical importance of our findings. 43, 44 While we are still exploring molecular pathways involved in SARS-CoV-2infection-triggered CNS responses and its related neuropsychiatric manifestation, 45 we need to identify a clear path forward to specifically reduce the impact of COVID-19 on AD and MCI patients. 46 Future studies are needed to understand the pathological changes that may explain increased occurrence of COVID-19 among AD and MCI patients. We thank Sarah Daley for helpful discussions. All authors have declared that no competing interests exist. We are reporting a retrospective study of medical records. 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