Hospital-treated infectious diseases and the risk of dementia: multicohort study with replication in the UK Biobank
Authors: Sipilä Pyry N , Heikkilä Nelli , Lindbohm Joni V , Hakulinen Christian , Vahtera Jussi , Elovainio Marko , Suominen Sakari , Väänänen Ari , Koskinen Aki , Nyberg Solja T , Pentti Jaana , Strandberg Timo E. , Kivimäki Mika 
Published: April 2020

SummaryBackgroundInfectious 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.MethodsFor 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.FindingsIn 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).InterpretationGram-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.FundingUK Medical Research Council, US National Institute on Aging, NordForsk, Academy of Finland, Helsinki Institute of Life Science.Research in contextEvidence before this studyInfectious diseases have been hypothesised in the aetiology of dementia. We searched PubMed on 2 April 2020 for observational studies and systematic reviews using the search terms ((Alzheimer* OR dementia) AND infectio* AND ((systematic[sb]) OR (Observational Study[ptyp])) without restrictions on language or publication date. We also searched the reference lists and citations of relevant articles. In observational studies, infectious diseases in general and specific bacterial (sepsis, septicaemia, bacteraemia, pneumonia, osteomyelitis, urinary tract infection, cellulitis, syphilis, and Borrelia burgdorferi and Chlamydia pneumoniae infections) and viral infections (hepatitis C infection, HIV) are linked to an increased risk of dementia. Additionally, there was suggestive evidence for associations of herpesvirus infections, Toxoplasma gondii parasite infection, and poor oral health with dementia. However, no large-scale studies assessed a wide range of different types of infectious diseases systematically in a single analytical setting and with adequate control for potential sources of bias, such as reverse causation resulting from the systemic changes related to the preclinical stages of dementia that increase susceptibility to infectious diseases.Added value of this studyIn this multicohort study, the primary analysis was based on individual-level data from 273 125 dementia-free community-dwelling participants with a median follow-up of 19 years. We ascertained 528 different infectious diseases before dementia onset using national hospital inpatient records and categorised them by causative microorganism (bacteria, viruses), disease invasiveness (invasive vs localised bacterial infections), and subtype (extracellular vs intracellular lifestyle and cell wall structure of bacteria, and type of virus). When reverse causation was minimised by analysing only infections that occurred more than 10 years before dementia onset, the relative risk of dementia was modest for all bacterial infections combined (hazard ratio [HR] 1·27; 95% confidence interval [CI] 1·14–1·41) and for all viral infections combined (HR 1·19; 95% CI 0·87–1·62). The associations of bacterial infections with dementia did not differ by the invasiveness of the infection (invasive vs localised infections) or extracellular vs intracellular lifestyle of the causative microorganism. In analysis of specific diagnostic groups, robust and stronger long-term associations with dementia were observed for Gram-negative bacterial infections (HR 1·64, 95% CI 1·25–2·14 for full follow-up; HR 1·67, 95% CI 1·13–2·48 from year 10 onwards) and herpesvirus infections (HR 1·96, 95% CI 1.31–2.93 full follow-up; HR 1·92, 95% CI 1·11–3·32 from year 10 onwards). These associations remained after controlling for comorbidities and potential confounders and were replicated in an independent cohort of 492 146 individuals from the UK Biobank (median follow-up 9·0 years) with stronger relations observed for vascular dementia than Alzheimer’s disease.Implications of all the available evidenceGram-negative bacterial infections and herpesvirus infections seem to be robust long-term risk factors for dementia. Further mechanistic and molecular research is warranted to clarify the potential role of Gram-negative bacterial infections and herpesvirus in neurodegeneration and the aetiology of dementia.