Associations of hospital-treated infections with subsequent dementia: nationwide 30-year analysis

Abstract

Infections, which can prompt neuroinflammation, may be a risk factor for dementia^1-5. More information is needed concerning associations across different infections and different dementias, and from longitudinal studies with long follow-ups. This New Zealand-based population register study tested whether infections antedate dementia across three decades. We identified individuals born between 1929 and 1968 and followed them from 1989 to 2019 (n = 1,742,406, baseline age = 21-60 years). Infection diagnoses were ascertained from public hospital records. Dementia diagnoses were ascertained from public hospital, mortality and pharmaceutical records. Relative to individuals without an infection, those with an infection were at increased risk of dementia (hazard ratio 2.93, 95% confidence interval 2.68-3.20). Associations were evident for dementia diagnoses made up to 25-30 years after infection diagnoses. Associations held after accounting for preexisting physical diseases, mental disorders and socioeconomic deprivation. Associations were evident for viral, bacterial, parasitic and other infections, and for Alzheimer's disease and other dementias, including vascular dementia. Preventing infections might reduce the burden of neurodegenerative conditions.

Extended Data Fig. 1

To address the potential for ascertainment bias as well as reverse-causation related to dementia’s long pre-diagnosis phase, we estimated associations across varying follow-up intervals from the index infection (0–1, 1–5, 5–10, 10–15, 15–20, 20–25, and 25–30 years). Increased risk of dementia was observed across varying follow-up intervals from infection, from 0–1 years to 25–30 years. Analyses comprised 1,732,080 individuals; individuals with dementia diagnoses that predated infection diagnoses were excluded. Estimates are hazard ratios. Error bars indicate 95% confidence intervals. Follow-up intervals were non-overlapping, such that dementia risk estimated for a particular time interval considered only dementia diagnoses made in the specified interval, and did not include risk in the prior years.

Extended Data Fig. 2

In secondary analyses to test for a dose-response pattern, we counted infection-related hospital admissions and infection types across a 20-year exposure period (July 1989-June 2009), and as outcome ascertained dementia diagnoses across a 10-year follow-up period (July 2009-June 2019). We used Poisson regression models with relative risks to estimate the associations between number of infection-related hospital admissions and number of infection diagnoses of different types with subsequent dementia, controlling for mental disorders and physical diseases diagnosed before the index infection. Individuals who accumulated more infection-related hospital admissions (a) and more infection diagnoses of different types (b), across a 20-year exposure period, were more likely to be diagnosed with dementia in the 10-year follow-up period. Analyses excluded the 169,983 individuals who received a dementia diagnosis, died, or left the country during the exposure period. Error bars indicate 95% confidence intervals.

Figure 1.. Distributions of age-at-first-diagnosis for infection and dementia.

The figure shows the degree of temporal separation between first inpatient-hospital diagnoses of infection and dementia. Box plots display the median, first and third quartiles, and bottom 1^st and upper 99^th percentiles of the distributions of age-at-first-diagnosis, within the total population, men, and women. The confidentiality rules of Statistics New Zealand do not permit reporting of minimum and maximum values. Distributions were calculated among individuals who received both an infection and a dementia diagnosis during the observation period (N=24,696).

Figure 2.. Overrepresentation of dementia among individuals with an infection.

The prevalence of dementia diagnoses was higher among individuals diagnosed with an infection than among those without an infection diagnosis. This was the case in the total population (A) and among men (B) and women (C) of all ages. Estimates were calculated over the 30-year observation period. Counts were randomly rounded to a base of three per the confidentiality rules of Statistics New Zealand. Therefore, counts do not always sum to totals. Age ranges indicate ages during the 30-year observation period.

Figure 3.. Specificity of associations.

Infections of different types were associated with subsequent onset of any dementia (A), and infections were associated with Alzheimer’s disease, other dementias (e.g., vascular dementia, Parkinson’s-disease dementia, frontotemporal dementia), and unspecified dementias (B). Estimates are hazard ratios. Error bars indicate 95% confidence intervals. Total-population Ns including infection cases and controls were 1,316,880 (viral infection), 1,489,080 (bacterial infection), 1,288,707 (parasitic infection), and 1,538,523 (other infection). Total-population Ns including dementia cases and controls were 1,710,144 (Alzheimer’s disease), 1,716,513 (other dementia), and 1,727,412 (unspecified dementia). Controls were individuals without any infection diagnosis (Panel A) and individuals without any dementia diagnosis (Panel B). Due to computational constraints, hazard models could not be estimated in the total population. Total-population estimates were derived using meta-analysis to pool associations across four randomly-selected 25% subsets of males and of females. Associations estimated within subsets controlled for birth year, and for pre-existing metal-disorder and chronic-physical-disease diagnoses (see Methods). Because anti-dementia drug prescriptions in pharmaceutical records do not permit determination of dementia subtype, diagnoses of Alzheimer’s disease and other dementias were ascertained using ICD-10 and corresponding ICD-9 codes from public-hospital and mortality records; dementias with diagnostic codes of “unspecified” in hospital or mortality records and those ascertained only through pharmaceutical prescriptions were coded as unspecified. Associations by age and sex are shown in Supplementary Tables 1 and 2.