Risk of Major Types of Dementias Following Hospital-Diagnosed Infections and Autoimmune Diseases

Abstract

Background: Population-based studies have shown an increased risk of dementia after infections, but weaker links were reported for autoimmune diseases. Evidence is scarce for whether the links may be modified by the dementia or exposure subtype.

Objective: We aimed to investigate the association between infections and/or autoimmune diseases and rates of major types of dementias in the short- and long terms.

Methods: Nationwide nested case-control study of dementia cases (65+ years) diagnosed in Denmark 2016-2020 and dementia-free controls. Exposures were hospital-diagnosed infections and autoimmune diseases in the preceding 35 years. Two groups of dementia cases were those diagnosed in memory clinics (MC) and those diagnosed outside memory clinics (non-memory clinic cases, NMC).

Results: In total, 26,738 individuals were MC and 12,534 were NMC cases. Following any infection, the incidence rate ratio (IRR) for MC cases was 1.23 (95% CI 1.20-1.27) and 1.70 for NMC cases (1.62-1.76). Long-term increased rates were seen for vascular dementia and NMC cases. IRRs for autoimmune diseases were overall statistically insignificant.

Conclusions: Cases with vascular dementia and not Alzheimer's disease, and a subgroup of cases identified with poorer health have increased long-term risk following infections. Autoimmune diseases were not associated with any type of dementia. Notably increased risks (attributed to the short term) and for NMC cases may indicate that immunosenescence rather than de novo infection explains the links. Future focus on such groups and on the role of vascular pathology will explain the infection-dementia links, especially in the long term.

Keywords: Alzheimer’s disease; autoimmune disease; epidemiology; immunosenescence; infection; population-based; reverse causality; vascular dementia.

Fig. 1

Population flow chart. Memory clinic dementia cases: Of all the controls, 75,430 were unique individuals (i.e., there were repeated controls), and 1,494 controls became cases after index date at which point, they were matched with 3 new controls (and are counted among the 26,738 cases). Non-memory clinic dementia cases: Of all the controls, 36,179 were unique individuals and 1,266 controls became cases after index date.

Fig. 2

Dementia IRRs following infections in memory clinic and non-memory clinic cases, and with a 10-year lag period. The figure presents the incidence rate ratios (IRRs) of dementia following infections for: non-memory clinic all-cause dementia cases (stratified by infection burden, sex, and age at index date), memory clinic all-cause dementia cases (stratified by infection burden, sex, and age at index date), and memory clinic Alzheimer’s disease (AD) cases, vascular dementia (VaD), other dementias, and unspecific etiology cases (further stratified by infection burden in each). The first (left) forest plot represents the adjusted IRRs for all dementia groups when no lag period was applied. The second (right) forest plot represents the adjusted IRRs for all dementia groups when a 10-year lag period was applied. IRRs were adjusted for highest attained educational level, stroke, myocardial infarction, hypertension, diabetes, and hypercholesterolemia (with age at index date and sex as matching variables, and the regression model accounted for this matching).

Fig. 3

Dementia IRRs following infections by type of infection in memory clinic and non-memory clinic cases, and with a 10-year lag period. The figure presents the incidence rate ratios (IRRs) of dementia following infections, stratified by infection type for: non-memory clinic all-cause dementia cases, memory clinic all-cause dementia cases, memory clinic Alzheimer’s disease (AD) cases, vascular dementia (VaD), other dementias, and unspecific etiology cases. “Other” category includes other types of infection than viral and bacterial and infections that were judged as not specific to either bacterial or viral alone. “Mixed” category includes cases and controls with co-infections of several types (e.g., bacterial and other). The first (left) forest plot represents the adjusted IRRs for all dementia groups when no lag period was applied. The second (right) forest plot represents the adjusted IRRs for all dementia groups when a 10-year lag period was applied. IRRs were adjusted for highest attained educational level, stroke, myocardial infarction, hypertension, diabetes, and hypercholesterolemia (with age at index date and sex as matching variables, and the regression model accounted for this matching).

Fig. 4

Dementia IRRs following autoimmune diseases in memory clinic and non-memory clinic cases. Figure presents the incidence rate ratios (IRRs) of dementia following autoimmune diseases for: non-memory clinic all-cause dementia cases (stratified by sex, age at index date, and disease type), memory clinic all-cause dementia cases (stratified by sex, age at index date, and disease type), and memory clinic Alzheimer’s disease (AD) cases, vascular dementia (VaD), other dementias, and unspecific etiology cases (further stratified by disease type in each). The ‘mixed’ category includes cases and controls with both organ-specific and systemic diseases. IRRs were adjusted for highest attained educational level, stroke, myocardial infarction, hypertension, diabetes, and hypercholesterolemia (with age at index date and sex as matching variables, and the regression model accounted for this matching).