Hospital-treated infectious diseases and the risk of dementia: multicohort study with replication in the UK Biobank

Abstract

Background: Infectious diseases have been hypothesised to increase the risk of dementia. However, the evidence is sparse, captures only a limited range of infectious diseases, and relies on short follow-up periods. We assessed a wide range of severe (hospital-treated) bacterial and viral infections and their subtypes as risk factors for dementia in three large cohorts followed up for almost two decades and replicated the main findings in the UK Biobank. Methods: For primary analysis, we pooled individual-level data from three prospective cohort studies with a median follow up of 19 years (from 1986-2005 to 2012-2016) and a total of 273 125 dementia-free community-dwelling participants. The replication analysis with the UK Biobank was based on 492 146 individuals (median follow-up 9.0 years from 2006-2010 to 2018). We ascertained exposure to infectious diseases and their subtypes before dementia onset using linked records from national hospital inpatient registers. Incident dementia was identified from linked hospital inpatient and outpatient records, medication reimbursement entitlements, and death certificates. Findings: In the primary analysis based on 5.3 million person-years at risk, 88 099 participants had a hospital-treated infection before dementia onset and 3064 developed dementia. Gram-negative bacterial infections (hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.25-2.14) and herpesvirus infections (HR 1.96; 95% CI 1.31-2.93) were robustly associated with an increased risk of dementia. For these infections, the relative risk of dementia remained similar when reverse causation and ascertainment biases were minimised by assessing only new dementia cases that occurred more than 10 years after the infection, and when comorbidities and potential confounders were considered. The associations were replicated in the UK Biobank with stronger relations observed for vascular dementia than Alzheimer's disease. In contrast to gram-negative bacterial and herpesvirus infections, the hazard ratio for all bacterial infections combined attenuated from 1.60 (95% CI 1.48-1.72) to 1.27 (95% CI 1.14-1.41) when bias was minimised. For all viral infections, the corresponding attenuation was from HR 1.63 (95% CI 1.32-2.00) to 1.19 (95% CI 0.87-1.62). Interpretation: Gram-negative bacterial infections and herpesvirus infections were associated with a moderately increased risk of dementia both in the short- and long-term. Hospital-treated bacterial and viral infections in general had only modest long-term associations with incident dementia.

Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus

“…In a seminal study published in 2009, recent inflammatory events were associated with increased levels of peripheral immune markers and a twofold increase in the rate of cognitive decline over a 6-month period 58 . With regard to longer-term outcomes, a recent study showed that a history of infections requiring hospital treatment was associated with future development of dementia, even when analyses were limited to individuals in whom dementia was diagnosed more than 10 years after the infection 59 . Of note, such infections were more strongly associated with vascular dementia than with AD dementia, suggesting that infection-related mechanisms involve both inflammatory and vascular pathways 59 .…”

Progressive cognitive impairment after recovery from neuroinvasive and non-neuroinvasive Listeria monocytogenes infection

“…The key findings are that individuals hospitalized for CNS infections (bacterial or viral), as well as bacterial infections confined to the periphery, e.g. urinary tract, skin, and respiratory, had significantly greater risk of developing dementia over a prolonged observational period than did those with no hospitalizations for infection (7,54,55). Moreover, CNS infections inflicted the greatest risk of dementia with an adjusted hazard ratio (aHR) of 3.01 [95% CI 2.07 -4.37], even though non-CNS infections also conferred an excess risk (aHR 1.47 [95% CI 1.36 -1.59] (7).…”

“…Despite a declining incidence of neurological diseases caused by meningitis in developed countries (4, 5), meningitis remains the 4 th leading cause of neurological disability-adjusted life-years globally (6). Additionally, recent data from a Finnish multicohort observational study found that individuals experiencing a CNS infection were 3-times more likely than uninfected individuals to develop dementia over a median follow-up period of 15.4 years (7). Host inflammatory responses are key drivers of post-infectious neurological dysfunction (8)(9)(10)(11).…”

Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation

“…The majority of these patients are afflicted with SAE. Studies involving large patient cohorts provided robust evidence for the increased risk of developing dementia after severe systemic inflammation 1 . Post-infectious long-term cognitive dysfunction results not only in major disability of afflicted patients but causes also an immense burden on primary caregivers and the health care system 2 .…”

“…Growing evidence suggests that severe systemic infections may lead to long-term cognitive dysfunction with the risk of developing dementia. 1,2 Sepsis as the most severe manifestation of systemic infection is defined as a life-threatening organ dysfunction caused by an overwhelming and dysregulated host response to inflammation. 3 Sepsis is a world-wide health problem with increasing incidence and high mortality.…”