Is exposure to infections or autoimmune diseases associated with dementia incidence?

In a recent study published in JAMA Network Open, researchers explored the relationships between hospital-identified infections, autoimmune diseases, and the onset of dementia, emphasizing the role of systemic inflammation.

Study: Hospital-Diagnosed Infections, Autoimmune Diseases, and Subsequent Dementia Incidence. Image Credit: LightField Studios/Shutterstock.com

Background 

Infections have been considered as potential causes of dementia, especially Alzheimer’s disease (AD). While some studies target specific infections or pathogens, it is uncertain whether specific agents are the cause or if infection-induced inflammation is the risk factor.

Many studies rely on postmortem brain analysis, raising temporality concerns, and often have short follow-ups with select populations.

Recent research suggests a broader infection risk tied to dementia, with some pointing to systemic inflammation, not just specific agents. Systemic inflammation is linked to heightened dementia risk, and while studies on autoimmune diseases suggest a similar inflammation-induced risk, the results vary.

Further research is needed to clarify the shared inflammatory signals between infections, autoimmune diseases, and dementia onset.

About the study 

Researchers used Danish national registries, including the National Patient Register (NPR), the Psychiatric Central Research Register (PCRR), and the National Prescription Register to study potential links between infections, autoimmune diseases, and dementia.

The study considered individuals born from 1928 to 1953 and living in Denmark by January 1, 1978, excluding prior dementia or HIV cases.

Exposure to infections or autoimmune diseases was gaged through hospital records, capturing the type, frequency, and site of infections or the specific autoimmune diseases diagnosed. The primary outcome was the onset of dementia after age 65, detected either through registry data or by monitoring the redemption of antidementia prescriptions.

Apart from the central variables, the analysis accounted for sex, age, education level at age 50, and relevant comorbidities.

Poisson regression was applied to study the time to the initial dementia diagnosis. Adjustments in the data were made for the above factors, with supplementary tests to discern if infections influenced the risk of autoimmune diseases and vice versa.

After the initial analysis, they examined dementia rates based on the first recorded infection. They conducted four sensitivity analyses to validate their findings: evaluating IRRs over two-time frames, assessing mortality rates post-exposure, discarding ambiguous infection codes, and considering exposures before age 50. The study covered 1978 to 2018, amid data analysis between May 2022 and January 2023.

Study results 

In the present comprehensive study spanning 14,093,303 person-years with 1,493,896 participants, of which 51% were women, 45% or 677,147 individuals were diagnosed with infections, and 9% or 127,721 individuals were diagnosed with autoimmune diseases starting from age 50.

Additionally, 5% or 75,543 participants were registered with all-cause dementia beginning at age 65, typically diagnosed at the age of 77. Notably, 51% of the infections were found in men, whereas 61% of autoimmune disease cases were in women.

Those diagnosed with either infections or autoimmune diseases were generally older when diagnosed with dementia than others.

Regarding specific diseases, respiratory infections were predominant, trailed by urinary and gastrointestinal infections. The most frequently diagnosed autoimmune diseases were polymyalgia rheumatica and rheumatoid arthritis.

There was a notable increased incidence rate ratio (IRR) for dementia in individuals with any infection compared to those without, with the rate rising with the number of infections. This elevated IRR was observed shortly after the infection and persisted over a longer term, though the increase was more significant within the initial five years.

Contrastingly, individuals with autoimmune diseases showcased a modest rise in IRR for dementia, with the impact being slightly pronounced in women. However, the overall IRR growth was relatively insubstantial, especially after factoring in infections.

No discernible dose-response relationship was evident with the burden of autoimmune diseases. Only a handful of autoimmune disease categories displayed a statistically significant IRR, but the magnitude of this relationship remained minor post-infection adjustment.

When setting a unified reference group for analysis, the trends observed were consistent with the earlier findings, reiterating the pronounced impact of infections on dementia IRR.

The supplementary sensitivity tests revealed heightened mortality rate ratios post-infection and post-autoimmune disease diagnosis, with infections manifesting more significant ratios. Nonetheless, the overarching results of the study remained consistent regardless of the specific definitions and parameters employed.

Conclusions 

In a cohort study of around 1.5 million individuals spanning over 40 years, researchers found that hospital-diagnosed infections at nearly every site correlated with heightened dementia rates, especially in the short term, displaying a dose-response relationship.

In contrast, the increase in rates for autoimmune diseases was marginal. This research is groundbreaking as it comprehensively assesses infection sites, evaluates short- and long-term risks, and examines the impact of infection and autoimmune disease burdens.

Uniquely, this study simultaneously evaluated two exposures in a single nationwide cohort, providing valuable insights into their influence as dementia risk determinants and potential mechanisms involved.