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COVID‐19 breakthrough infections and hospitalizations among vaccinated patients with dementia in the United States between December 2020 and August 2021

Abstract Introduction There is lack of data on COVID‐19 breakthrough infections in vaccinated patients with dementia in the United States. Methods This is a retrospective cohort study of 262,847 vaccinated older adults (age 73.8 ± 6.81 years old) between December 2020 and August 2021. Results Among the fully vaccinated patients with dementia, the overall risk of COVID‐19 breakthrough infections ranged from 8.6% to 12.4%. Patients with dementia were at increased risk for breakthrough infections compared with patients without dementia, with the highest odds for patients with Lewy body dementia (LBD) (adjusted odds ratio or AOR: 3.06, 95% confidence interval or CI [1.45 to 6.66]), followed by vascular dementia (VD) (AOR: 1.99, 95% CI [1.42 to 2.80]), Alzheimer's disease (AD) (1.53, 95% CI [1.22 to 1.92]), and mild cognitive impairment (MCI) (AOR: 1.78, 95% CI [1.51 to 2.11]). The incidence rate of breakthrough infections among fully vaccinated patients with dementia increased since December 2020 and accelerated after May 2021. The overall risk for hospitalization after breakthrough infections in patients with dementia was 39.5% for AD, 46.2% for VD, and 30.4% for MCI. Discussion These results highlight the need to continuously monitor breakthrough severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections and outcomes in vaccinated patients with dementia.

Alzheimer's disease (AD) and vascular dementia (VD) were at increased risk for COVID-19 infection and severe outcomes, especially among African Americans, 13 even after controlling for demographic factors and comorbidities.
In the United States, vaccines have been approved to prevent COVID-19 infection including two messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna and an adenovirus vaccine by Johnson & Johnson (J&J). [14][15][16] Clinical trial data showed an efficacy of 95% for the Pfizer-BioNTech vaccine, 14 94.1% for the Moderna vaccine, 15 and 66.3% for the J&J. vaccine in preventing COVID-19 infection. 16 However, both older adults and patients with dementia were under-represented in clinical trials for COVID-19 vaccines. For example, in the clinical trial for Pfizer-BioNTech vaccine, the median age for the 37,706 participants was 52 years and included only 18 individuals with dementia (0.05%). 14 Vaccines are very effective, but breakthrough infections have been recorded, [17][18][19][20] highlighting the need to understand the populations that might be most vulnerable, including patients with AD and other types of dementia, as we have entered a worrisome new phase of the pandemic with emerging virus variants. [21][22][23] 2 METHODS

Database description and study population
We used the cloud-based TriNetX Analytics network platform, which allows access to de-identified data of > 84 million unique patients from 61 health care organizations in the United States. 24 Multiple studies have used TriNetX Analytics network platform to study risk, disparity, sequelae, temporal trends, clinical characteristics, and outcomes of COVID-19. [25][26][27][28][29] Our study population comprised 262,847 older adults TriNetX Analytics is a federated cloud-based network providing web-based real-time secure access to patient electronic health records (EHRs) from hospitals, primary care and specialty treatment providers of diverse geographic locations, age groups, race/ethnic groups, and income levels. Although the data are de-identified, end-users can use TriNetX Analytics built-in statistical and informatics functions to work on patient-level data for cohort selection, propensity-score matching, analyzing incidence and prevalence of events in a cohort, and comparing characteristics and outcomes between matched cohorts. Because this study used only de-identified patient records and did not involve the collection, use, or transmittal of individually identifiable data, this study was exempted from institutional review board approval.
The status of COVID-19 was based on the 10th revision of the International Classification of Diseases (ICD-10) diagnosis code of "Covid-

Statistical analysis
The following analyses were performed. For each analysis, the outcome of breakthrough COVID-19 infection was examined 14 days after vaccination. All statistical analyses were performed on the TriNetX Analytics Platform at significance set at P-value < .05 (two-sided).
The list of covariates, and their standardized names codes and data types that are used in the TriNetX database are described in Table 1.
The odds of breakthrough infections in the vaccinated patients with dementia were calculated by comparing to those without dementia, after propensity score matching (1:1 using a nearest neighbor greedy matching) for covariates listed in Table 1. Separate analysis was performed for AD, VD, LBD, FTD, and MCI.  Table 1.
Separate analyses were done for specific dementia subtypes and non-dementia.
• The overall risks for hospitalizations in patients who had breakthrough infections ("breakthrough cohort") were examined and compared with those in patients who had no breakthrough infections ("non-breakthrough cohort"). Two cohorts were propensityscore matched for the covariates listed in Table 1. Hospitalizations were followed starting on the day of breakthrough infections for the breakthrough cohort or 14 days after full vaccination for the nonbreakthrough cohort up to August 1, 2021. Kaplan-Meier analysis was performed to estimate the probability of hospitalizations. Comparison of outcomes between patients with versus without breakthroughs were made using Cox proportional hazards model. The proportional hazard assumption was tested using the generalized Schoenfeld approach. When the assumption was violated, the Cox model was stratified by the variate violating the proportional hazards assumption. The hazard ratio (HR) and 95% confidence interval (CI) were calculated. Separate analyses were done for AD, VD, and MCI and non-dementia. LBD and FTD were not examined due to limited sample sizes. Mortality was not examined due to small sample sizes. For The Health Insurance Portability and Accountability Act of 1996 (HIPAA)-compliant statistical de-identification, the TriNetX platform does not report actual cohort counts <10. The numbers of deaths in the cohorts during the study period were all <10, preventing an accurate estimate of the death rates.

Patients' characteristics (as of August 1, 2021)
The study population comprised 262,847 vaccinated older adults (age ≥65 years). Demographic characteristics of the patients and sample sizes are shown in Table 2. Patients with dementia including AD and VD were older than those without dementia. There were more women in the vaccinated population except for patients with LBD. Compared to other cohorts, the cohort with VD had more African Americans (25.9%). The prevalence of adverse socio-economic status and nursing home stay was also higher in the dementia population than in patients without dementia.
Patients with dementia, regardless of subtype, had a higher prevalence of comorbidities that are demonstrated risk factors for COVID-19 including hypertension, obesity, type 2 diabetes, heart diseases, cerebrovascular diseases, cancers, chronic respiratory diseases, liver diseases, chronic kidney diseases, substance use disorders (including tobacco and alcohol use), and neuropsychiatric disorders. For example, the prevalence of hypertension in vaccinated patients with AD and VD was 69.9% and 79.7%, as compared to 37.9% in vaccinated patients without dementia.

Overall accumulated risks for breakthrough infections in the vaccinated patients between December 2020 and August 2021
Between December 2020 and August 2021, the overall risk of breakthrough infections beginning 14 days following vaccination in older adults without dementia was 5.6%. The risks of breakthrough infections were significantly higher in patients with various types of dementias: 10.3% for AD, 12.5% for VD, 14.3 for LBD, 11.8% for FTD, and 11.6% for MCI (Table 3).  (Table 3). Subsequent analyses focused on breakthrough infections in the fully vaccinated population.

Dementia is associated with increased risk of breakthrough infections in vaccinated population between December 2020 and August 2021
As seen in Table 2 Patients with dementia had a higher prevalence of comorbidities that are known risk factors for COVID-19 (Table 2). After further matching for these comorbidities, patients with dementia were no longer at a significantly increased risk for breakthrough infections compared with matched patients without dementia (Figure 1). These results document that the significantly higher risk for breakthrough infection in patients with dementia was largely accounted for by comorbidities that were prevalent in patients with dementia.

TA B L E 3
The overall risk of breakthrough infections in vaccinated and fully vaccinated older adult populations 14 days after vaccination between December 2020 and August 2021

Time trends of breakthrough infections in fully vaccinated patients with dementia stratified by age, race, and gender between December 2020 and August 2021
We examined how breakthrough infections among the fully vaccinated older adults with and without dementia evolved between December 2020 and August 2021. The rate of new cases of breakthrough infections, measured by cases/person-day, in the fully vaccinated patients with AD, VD, and MCI, and older adults without dementia steadily increased from December 2020 to August 2021, in all age, race, and gender groups (Figure 2). Compared to MCI and non-dementia patients, patients with AD and VD had higher incidence rates with steeper increases after May 2021. LBD and FTD patients were not examined due their limited sample sizes.

Racial, gender, and age disparities of breakthrough infection among fully vaccinated patients with dementia
We then investigated how age, gender, and race affected the risk of

Overall risks for hospitalizations among patients with dementia who had breakthrough infections
We compared the overall risks of hospitalizations in the fully vacci- propensity-score matched for demographics (age, gender, and race/ethnicity), adverse socioeconomic determinants of health (SDOHs), and nursing home stay status; (B) cohorts were propensity score matched for demographics (age, gender, race/ethnicity), adverse SDOHs, nursing home stay status, and comorbidities listed in Table 1 with MCI who had no breakthrough infections (HR: 41.9, 95% CI: 28.  In our previous study during the early stage of the pandemic (February to August 2020) when vaccines were not available, we reported marked racial disparities in COVID-19 risk in individuals with dementia, with African Americans showing more than two-fold higher risk than Caucasians, but we observed no gender and age disparities. 13 In contrast, this study shows significant age differences for breakthrough infections among fully vaccinated dementia patients as well as non-dementia patients, with older individuals (age ≥80 years) being more susceptible to breakthrough infections than those aged 65 to 79 years. This might reflect the age-related decline in immunity that not only would increase susceptibility to infection but also reduce the prophylactic efficacy of vaccinations. 30 Rong Xu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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