The risk of developing Alzheimer’s disease almost doubled in older people during the one-year period following COVID-19 infection

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Older people who were infected with COVID-19 show a substantially higher risk – as much as 50% to 80% higher than a control group – of developing Alzheimer’s disease within a year, according to a study of more than 6 million patients 65 and older.

In a study published today in the Journal of Alzheimer’s Disease, researchers report that people 65 and older who contracted COVID-19 were more prone to developing Alzheimer’s disease in the year following their COVID diagnosis. And the highest risk was observed in women at least 85 years old.

The findings showed that the risk for developing Alzheimer’s disease in older people nearly doubled (0.35% to 0.68%) over a one-year period following infection with COVID. The researchers say it is unclear whether COVID-19 triggers new development of Alzheimer’s disease or accelerates its emergence.

“The factors that play into the development of Alzheimer’s disease have been poorly understood, but two pieces considered important are prior infections, especially viral infections, and inflammation,” said Pamela Davis, Distinguished University Professor and The Arline H. and Curtis F. Garvin Research Professor at the Case Western Reserve School of Medicine, the study’s coauthor.

“Since infection with SARS-CoV2 has been associated with central nervous system abnormalities including inflammation, we wanted to test whether, even in the short term, COVID could lead to increased diagnoses,” she said.

The research team analyzed the anonymous electronic health records of 6.2 million adults 65 and older in the United States who received medical treatment between February 2020 and May 2021 and had no prior diagnosis of Alzheimer’s disease.

They then divided this population two groups: one composed of people who contracted COVID-19 during that period, and another with people who had no documented cases of COVID-19. More than 400,000 people were enrolled in the COVID study group, while 5.8 million were in the non-infected group.

“If this increase in new diagnoses of Alzheimer’s disease is sustained, the wave of patients with a disease currently without a cure will be substantial, and could further strain our long-term care resources,” Davis said.

“Alzheimer’s disease is a serious and challenging disease, and we thought we had turned some of the tide on it by reducing general risk factors such as hypertension, heart disease, obesity and a sedentary lifestyle.

“Now, so many people in the U.S. have had COVID and the long-term consequences of COVID are still emerging. It is important to continue to monitor the impact of this disease on future disability.”

Rong Xu, the study’s corresponding author, professor of Biomedical Informatics at the School of Medicine and director of the Center for AI in Drug Discovery, said the team plans to continue studying the effects of COVID-19 on Alzheimer’s disease and other neurodegenerative disorders—especially which subpopulations may be more vulnerable—and the potential to repurpose FDA-approved drugs to treat COVID’s long-term effects.

Previous COVID-related studies led by CWRU have found that people with dementia are twice as likely to contract COVID; those with substance abuse disorder orders are more likely to contract COVID; and that 5% of people who took Paxlovid for treatment of COVID symptoms experienced rebound infections within a month.


Using a nationwide population-based database in South Korea, COVID-19 survivors were shown to be associated with a higher incidence of overall dementia and this association was more evident in COVID-19 survivors who were admitted to hospital due to COVID-19 or who underwent oxygen therapy. Moreover, the association between dementia and COVID-19 survivorship was statistically significant for AD and other types of dementia, but not for VD.

In the subgroup analyses, the increased association of dementia was more evident in the female group, older age group (≥60 years old), CCI ≥ 3 group and those with underlying diabetes and CVD among the COVID-19 survivors. The results of this study suggest that COVID-19 survivors with these risk factors may have a increased risk for dementia, especially AD and other types of dementia, at approximately 6 months’ follow-up period.

Considering that COVID-19 has been suggested as a risk factor for the progression to dementia, especially AD [26], this is the first report to deduce that COVID-19 can be a risk factor for the diagnosis of dementia, such as AD, among survivors at 6 months’ follow-up.

A few possible mechanisms have been suggested to explain the effect of COVID-19 on the AD diagnosis in this study. COVID-19 is associated with a severe immune response and an increase in systemic cytokine levels [13]; systemic inflammation has been shown to promote cognitive decline and contribute to the pathogenesis of neurodegenerative diseases such as AD [27]. Moreover, SARS-CoV-2 also invades the CNS and is associated with neuroinflammation [28].

Previous studies have reported that SARS-CoV-2 directly causes viral encephalitis and SARS-CoV-2 was detected in the cerebrospinal fluid of patients, demonstrating the neuroinvasive potential of SARS-CoV-2 [29]. In the process of neuroinflammation, the coronavirus ORF3a protein is known to activate the NLRP3 inflammasome [30].

In turn, NLRP3 inflammasome-mediated neuroinflammation adversely affects beneficial immune functions in the brain and causes the pathological accumulation of neurodegeneration-associated peptides, such as fibrillar amyloid-β [31]. The pathological accumulation of amyloid-β peptide is known to be an important mechanism in the pathogenesis of AD [32]. In addition, activation of the NLRP3 inflammasome is known to directly induce or aggravate neurodegenerative processes that lead to functional impairment in AD [33].

In this study, COVID-19 survivors who were admitted to a hospital due to COVID-19 or who underwent oxygen therapy were associated with an increased risk of dementia, while those with no symptoms or mild symptoms were not, suggesting that the disease severity of COVID-19 might have affected the results. ICU admission and invasive treatment such as mechanical ventilator care for acute respiratory distress syndrome (ARDS) are known risk factors for cognitive decline [34].

In the current pandemic, due to SARS-CoV-2, a retrospective cohort study of 1591 COVID-19 patients admitted to the ICU in Italy showed that 88% of COVID-19 patients required mechanical ventilation [35]. Moreover, COVID-19 survivors who required oxygen therapy might have a higher viral load of SARS-CoV-2 than those with mild or no symptoms. This suggests that COVID-19 survivors who required hospitalization or oxygen therapy might have a higher possibility of sequalae such as neurodegenerative diseases, including AD [36].

The results of the subgroup analyses are also novel. Our study revealed that COVID-19 survivors with a higher underlying risk of dementia, due to diabetes, old age, female sex, higher CCI score and CVD were at a significantly higher risk of dementia. The risk factors for dementia diagnosis and COVID-19, such as old age and comorbidity status, are known to overlap [37].

Our study also reveals that COVID-19 survivors with an underlying risk of dementia are more vulnerable to the development of dementia [38]. For example, comorbidities, such as diabetes and cerebrovascular disease, were known risk factors for dementia, as our study reported similarly in COVID-19 survivors [39].

The HR of COVID-19 survivors for the risk of dementia was higher after excluding test-negative individuals in this study. In Table 1, the CCI was significantly higher in the control group (control population and test-negative individuals), while CCI did not significantly differ between COVID-19 survivors and the control population after excluding test-negative individuals as shown in Table S4. In South Korea, after extensive contact tracing for all COVID-19 patients before diagnosis by PCR test, the KDCPA tested all those individuals for COVID-19 who had been in direct or indirect contact with COVID-19 patients in the community or hospital [20].

Therefore, several older individuals had to be tested by PCR due to contact with with their children who were more active than the older people and were thus more likely to be test-positive or come into contact with COVID-19 patients. Moreover, if a patient in certain long-term facility care centers is diagnosed with COVID-19, all patients in the center undergo PCR testing for early detection of COVID-19, because they are a high-risk group for COVID-19 related death [40]. Therefore, the test-negative group comprised older patients with comorbidities and including these patients led to a higher prevalence of comorbidities in the control group as shown in Table 1.

Our study had some limitations. First, important parameters related to dementia risks, such as the body mass index, alcohol consumption and smoking history, were not included in this study because the NHIS database did not contain the relevant data. Smoking and alcohol use are known risk factors for the dementia diagnosis [41], the absence of which may have affected our results. Second, while we used multivariable adjustment with known and measured confounders, unmeasured and unknown confounders may have affected the results. For example, some comorbidities, such as hypertension or atrial fibrillation, were not adjusted for as confounders and it might have affected the results in this study.

Third, the severity of dementia was not evaluated in this study because of the limitations of the data source. Fourth, although treatment information such as that for oxygen therapy and hospital admission among COVID-19 survivors was used, the severity of the infection was not reflected accurately through the laboratory results. Fifth, although all patients with dementia should be registered in the NHIS DB to receive financial support for treatment expenses, some cases of dementia may have been missed.

For example, some individuals with mild dementia symptoms might not visit the outpatient clinic for diagnosis, which may affect the results of this study. Lastly, there was a medical surveillance bias in this study that affected the main result. As individuals who have undergone testing, as well as those who have been confirmed of having been tested, are more likely to be under medical surveillance, such individuals are more likely to be tested and be diagnosed with dementia.

The sensitivity analysis with removing those who tested negative for COVID-19 in Table 4 supports this medical surveillance bias. In other words, the HR in the sensitivity analysis tends to be higher than that in the main analysis, suggesting that individuals with positive or negative PCR test results are more likely diagnosed with dementia.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540001/


Original Research: Open access.
Association of COVID-19 with New-Onset Alzheimer’s Disease” by Pamela Davis et al. Journal of Alzheimer’s Disease

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