Severe infections may raise the risk of dementia independent of underlying noninfectious conditions, an observational Finnish registry study concludes.
University of Helsinki researchers compared 62,555 people aged 65 and older in 2016 who were diagnosed as having late-onset dementia from 2017 to 2020 with 312,772 matched controls without dementia.
“Severe infections have been linked to an increased risk of dementia, but both conditions often coexist with other illnesses that may confound this association,” the researchers wrote.
“Several plausible mechanisms have been proposed to explain this association, including disturbed peripheral-central immune crosstalk, which contributes to neuroinflammation; inflammation-induced blood-brain barrier dysfunction and related entry of neurotoxic plasma components, blood cells and pathogens into the central nervous system; and infection-related vascular mechanisms, such as platelet activation, inflammation-induced thrombosis, and endothelial dysfunction in the brain,” they added.
47% of dementia patients had history of at least one of 29 conditions
The average age of both patients and controls was 81years. After applying a one-year lag period, the team identified 29 hospital-treated conditions diagnosed one to 21 years before dementia that had a prevalence of at least 1% before dementia diagnosis and were strongly linked to increased dementia risk (confounder-adjusted rate ratio, at least 1.20).
Severe infections have been linked to an increased risk of dementia, but both conditions often coexist with other illnesses that may confound this association.
The conditions included nine injuries; six mental and behavioral disorders; five cardiovascular and three neurologic diseases; one endocrine, one metabolic, one eye, and one digestive disease; as well as urinary tract infection (UTI) and bacterial infection at an unspecified site.
A total of 47.0% of the 62,555 dementia patients had at least one of these conditions in the 21 years before dementia diagnosis, and 20.6% had at least two. The most common conditions were ischemic stroke (prevalence, 9.6%), brain injury (6.0%), and type 2 diabetes (4.9%).
The strongest links to dementia were seen for mental disorders due to brain damage or physical disease (rate ratio [RR], 3.76), Parkinson’s disease (RR, 3.24), and alcohol-related mental and behavioral disorders (RR, 1.87).
The RRs between infections and dementia were lower, at 1.22 for UTI and 1.21 for bacterial infection of unspecified site. On average, the conditions were diagnosed 4.7 to 11.8 years before dementia, with the earliest diagnosis for depression (11.8 years) and the latest for organic mental disorders (4.7 years). UTIs and bacterial infections of unspecified site occurred an average of 6.5 and 5.6 years before dementia diagnosis, respectively.
66% of dementia-related diseases tied to UTI risk
Of the 29 dementia-related diseases studied, 65.5% were tied to an increased risk of UTI, with the strongest associations for epilepsy (RR, 2.69), hemorrhagic stroke (RR, 2.69), and alcohol-related mental and behavioral disorders (RR, 2.61).
Ten diseases (34.5%) were linked to bacterial infections of unspecified site, most strongly other fluid, electrolyte, and acid-base balance disorders (RR, 2.57); retinal disorders of diseases classified elsewhere (RR, 2.46); and alcohol-related mental and behavioral disorders (RR, 2.30).
The associations among UTI, bacterial infection of another site, and dementia risk were not attributable to the underlying dementia-related diseases diagnosed before infection. The adjusted rate ratio (aRR) for UTI was 1.22 before and 1.19 after adjustment for underlying illnesses, while for bacterial infections of an unspecified site, the aRRs were 1.21 and 1.19, respectively.
The findings were similar across subgroups defined by sex and education and more robust for patients with early-onset dementia. The researchers cautioned that they weren’t able to directly assess psychosocial, behavioral, or biological confounders not captured in nationwide registries.
Potential role of infection-related inflammation
“This nationwide Finnish study identified several mental and physical diseases that are associated with an increased risk of dementia and showed that the increased incidence of dementia among individuals with severe infections is not attributable to these comorbid conditions,” the study authors wrote. “These results support the role of severe infections as independent risk factors for dementia.”
Intervention studies are required to establish whether preventing or effectively treating infections yields benefits for dementia prevention.
Pre-existing conditions are potentially important contributors to the link between infection and dementia, the researchers noted, because the average age of dementia diagnosis is older than 80 years, and thus people with dementia often have other conditions, many of which also pose an increased risk of infection.
The average interval from infection diagnosis to dementia was relatively short. This suggests that inflammation from infections severe enough to require hospital treatment may accelerate the preclinical stage of dementia rather than initiate neurodegeneration in a cognitively healthy person, they added.
Previous studies and natural experiments suggest that vaccination against infectious diseases might reduce or delay dementia onset.
“Overall, our findings support the possibility that severe infections increase dementia risk; however, intervention studies are required to establish whether preventing or effectively treating infections yields benefits for dementia prevention,” the researchers concluded.
