Severe infections associated with increased long-term risk of dementia

Evidence from a large long-term observational study involving nearly 750,000 individuals demonstrates a strong link between hospitalization for any infectious disease and increased dementia risk.

“Infections have been hypothesized to increase the risk of dementia. However, existing studies have included a narrow range of infectious diseases, relied on short follow-up periods, and provided little evidence for whether the increased risk is limited to specific dementia subtypes or attributable to specific microbes rather than infection burden,” wrote the researchers. “We aimed to compare the risk of Alzheimer's disease [AD] and other types of dementia across a wide range of hospital-treated bacterial and viral infections.”

Analysis was based on a primary cohort (n=260,490) consisting of pooled individual-level data of community-dwelling adults (age, ≥18 years), who had no dementia at study entry, from three prospective cohort studies in Finland (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study) and an independent replication cohort from the UK Biobank (n=485,708). [Lancet Infect Dis 2021;doi:10.1016/S1473-3099(21)00144-4]

In the primary cohort with a median follow-up of 15.5 years, 77,108 participants were hospitalized because of an infection, while 2,768 incident cases of dementia were identified from hospital records, medication reimbursement entitlements, and death certificates. Of these, 1,730 (62.5 percent) were diagnosed as AD, 209 (7.6 percent) as vascular dementia (VD), 114 (4.1 percent) as Parkinson's disease dementia, 102 (3.7 percent) as frontotemporal dementia, and 613 (22.1 percent) as other or unspecified dementia.

Hospitalization for any infectious disease was associated with increased dementia risk with an adjusted hazard ratio (aHR) of 1.48 (95 percent confidence interval [CI], 1.37 to 1.60. “Main findings from the primary cohort were replicated in the UK Biobank cohort [median follow-up, 7.7 years]. Infectious disease hospitalizations were associated with a 1.5-fold increased risk of dementia,” added the researchers.

“There was a dose-response relationship between multiple episodes of hospital-treated infection and increased dementia risk,” they reported. When including only dementia cases diagnosed ≥10 years after infection, the aHRs for incident dementia were 1.12 (95 percent CI, 0.97 to 1.29) for one infection, 1.15 (95 percent CI, 0.83 to 1.60) for two infections, and 1.68 (95 percent CI, 1.25 to 2.25) for three or more infections.

“Dementia risk did not vary substantially by type of infection: bacterial vs viral; bacterial infections with sepsis vs without sepsis, extracellular vs intracellular, Gram-positive vs Gram-negative; or herpes virus infection vs other persistent viral infections, although associations with acute viral infections were weaker. Both bacterial and viral infections were more strongly related to VD than AD,” wrote the researchers.

For extra–central nervous system (CNS) and CNS infections, the aHRs were 1.21 (95 percent CI, 1.09 to 1.35) and 1.44 (95 percent CI, 0.72 to 2.89), respectively. “In the supplementary analyses, infection-dementia associations did not differ by characteristics such as chronicity [acute vs chronic, including periods when the pathogen was inactive] and the infection’s capacity to enter the CNS, suggesting that the increased risk of dementia is not limited to CNS infections and that systemic infections are sufficient to affect the brain,” explained the researchers.

“In conclusion, our findings support the hypothesis that associations between infectious diseases and dementia are attributable to general inflammation rather than to specific microbes or infections in the CNS. Our data also suggest that mechanisms contributing to VD might be particularly important drivers of the infection-dementia association,” concluded the researchers.