Acute Infections That Lead to Hospitalization Increase the Risk for Dementia

Article In Brief

Protecting themselves from common infections and seeking treatment early if they do get sick could help patients avoid infections that may raise their risk of developing dementia.

People with a viral or bacterial infection severe enough to require hospitalization are at almost twice the risk of developing dementia years, and even decades, down the road, according to a new study published Jan. 9 in JAMA Network Open.

Researchers at the University of Minnesota who conducted the analysis said the findings suggest that people should protect themselves from common infections and get treatment early to avoid an infection that could require a hospital admission.

Senior study investigator Ryan Demmer, PhD, MPH, associate professor and co-director of the cardiovascular disease epidemiology and prevention training program in the division of epidemiology and community health at the University of Minnesota's School of Public Health, has been involved in the community-based Atherosclerosis Risk in Communities (ARIC) study that has followed more than 15,000 people for the past 30 years.

Study Details

The ARIC study began enrolling people in the observational study from 1987 to 1989 in Minneapolis, Maryland, North Carolina, and Mississippi. It collected detailed medical information over the decades. People who had dementia prior to their first identified infection were excluded from the study. Routine calls to record medical events, including infections that led to a hospitalization, were logged into the database. The researchers also had access to local hospital surveillance information and death records.

The investigators, led by Bruno Bohn, MPH, a PhD candidate in the division of epidemiology and community health at the University of Minnesota School of Public Health, noted the first occurrence of a hospitalization with infection (based on ICD codes in the hospital charts) and then looked at incident dementia listed in patients' medical charts from three to 20 years post-hospitalization. They also looked for infections (for a secondary analysis) that included respiratory, urinary tract, digestive tract, skin, blood or circulatory, and hospital-acquired infections.

Beginning in 2011, the ARIC investigators also conducted annual phone interviews; these increased to twice a year when they collected information on dementia. By 2016, they added in-person cognitive testing (and telephone cognitive questionnaires) to the ARIC study. They identified dementia cases using ICD codes in medical records and death certificates.

They had reams of health, medical, and lifestyle information from the study subjects that they ultimately used to adjust for their findings. Once they had a diagnosis of dementia, they looked at the mean age at baseline and the age the first symptoms of dementia appeared. They did separate analyses to adjust for apolipoprotein E4 (APOE4) genotype, history of transient ischemic attacks or stroke, other vascular risk factors, and sex.

Hospitalization with infection occurred in 38.2 percent of the participants. The most common infections were respiratory (19.7 percent) and urinary tract (12.4 percent.) Nineteen percent were diagnosed with dementia in later years. The average time to diagnosis was 25 years.

Those who developed dementia were more likely to be older, female, Black, or carriers of one or two copies of APOE4. (Infection was associated with increased dementia risk regardless of their APOE4 status.)

Without adjusting for time to dementia and other risk factors, patients hospitalized with an infection were almost two times more likely to develop dementia than those who did not have a history of a hospitalization for an infection. When excluding individuals who developed dementia very early (within three years of baseline) or very late (more than 20 years following infection), those who had any earlier infection that led to hospitalization had a more than fivefold higher risk for dementia. The risk varied when the researchers analyzed each ICD code.

“In these older ages when absolute risk increases, a doubling of the risk is quite relevant,” Dr. Demmer said.

Dr. Demmer explained that the most likely reason for the increased risk for dementia so long after a serious but acute infection is that the initial infection may have caused an inflammatory process that somehow had an impact. Growing evidence suggests that neuroinflammation and immune events in the periphery can affect pathological disease onset and progression that could take years, or decades, before clinical signs emerge. In addition, studies show that systemic or vascular inflammation also can drive neuroinflammation, although the mechanisms are not well understood.

The UK Biobank added the SARS-CoV-2 infection to the list of infections, suggesting that it may be associated with brain abnormalities and cognitive decline. Dr. Demmer and his colleagues are now studying the long-term cognitive problems people are experiencing after SARS-CoV-2 infection.

The scientists will continue their investigation into the events that may have led to the increased risk. They also acknowledged the limitations of observational studies, including that they only included infections that occurred during the study period, or those infections that led to a hospitalization. They also had no information on treatment that could have led to avoiding a hospitalization. Another possibility, they pointed out, is that the hospital experience itself might have put participants at higher risk.

“This is rich historical data,” Dr. Demmer added. “Everyone gets infections, but our data suggest that severe infections are important. However, there is also broader evidence in the literature that even mild to moderate infections can have long-term implications for health.”

Experts Comment

The results confirm the findings of other studies on these types of hospitalizations and the risk for dementia, said David Geldmacher, MD, professor and Warren Family Endowed Chair Of Neurology and division director for memory disorders and behavioral neurology at the University of Alabama at Birmingham. The authors describe the potential role of inflammation as a consequence of these infections, he said.

“We know that amyloid plaques build up years before clinical symptoms and that these plaques are a focal point of inflammation,” Dr. Geldmacher said. “They trigger microglia. If plaques are already present and there is systemic inflammation, that may accelerate or unmask dementia.”

“The findings are highly supportive of the idea that inflammation is a driver of dementia,” he added. “We need to do a better job of identifying the warning signs of severe infection and treat [them] immediately.” James M. Noble, MD, FAAN, associate professor of neurology at Columbia University Medical Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, said much remains to be understood about why people develop Alzheimer's disease.

“Diabetes and smoking cause low-grade inflammation over a long period of time, but we don't know the effects of acute infections that are short-lived but can trigger an intense inflammatory response,” he said. “This study lends support to the role of chronic and systemic inflammation that leads to the expression of Alzheimer's and other cognitive problems.”

Dr. Noble, author of Navigating Life with Dementia (Brain & Life Books), said it is also possible that an underlying neurodegenerative condition like Alzheimer's and an aging immune system could have led to a more severe infection that landed patients in the hospital. “The bottom line,” he said, “is that it comes down to preventative care.”