Mapping dementia risk factors and their interactions in Denmark: a nationwide cohort study

Background Although global estimates for dementia risk reduction are available, risk profiles might differ in a high-income, welfare-state setting. Few studies have been conducted that simultaneously estimate the prevalence of dementia risk factors and their associated risk of dementia within the same nationwide population. We aimed to estimate the relative risk of dementia and the population attributable fractions (PAFs) for 16 potentially modifiable risk factors, their combinations, and their interactions based on routinely collected health registry and survey data. Methods We conducted a nationwide cohort study based on data from Danish registries and the Danish National Health Survey (DNHS). The whole population, which included individuals born in or before 1957 who were alive, living in Denmark, and dementia-free at the start of follow-up, was followed up from age 65 years, or Jan 1, 2010 (whichever came last); individuals with additional data from the DNHS formed a subpopulation. Follow-up ended at death, emigration, dementia diagnosis, or on Dec 31, 2022 (whichever came first). The primary outcome was incident all-cause late-onset dementia diagnosis (age ≥65 years). We calculated dementia hazard ratios and PAFs for 16 risk factors (depression, traumatic brain injury, hospital-diagnosed infections, vision impairment, cardiovascular disease, sleep disorders, diabetes, hearing loss, hypercholesterolaemia, low education, hypertension, physical inactivity, social isolation, smoking, alcohol consumption, and obesity), as well as their combinations, and interactions between risk factors. Analyses were stratified by sex, birth cohorts, and educational level. Sensitivity analysis included accounting for reverse causation by splitting the risk time into less than 5 years and more than 5 years since exposure. Findings The whole population comprised 1 753 515 individuals, of whom 194 368 had additional DNHS data. The overall PAF for dementia in Denmark was 37·8% (95% CI 35·6–40·0) for the assessed risk factors. PAF for individual risk factors was highest for hospital-diagnosed infections (9·4% [9·3–9·4]), depression (8·7% [8·6–8·8]), and cardiovascular disease (CVD; 7·6% [7·6–7·7]). After accounting for reverse causation, the PAF for hospital-diagnosed infections was 7·0% (95% CI 6·9–7·0), and 5·7% (5·7–5·8) for depression. The apparently protective effect of obesity on dementia was also shown to be driven by reverse causation. The overall PAF was higher in males, 1948–57 birth cohorts, and individuals with low education. Risk factor profiles varied by sex and birth cohorts. Risk factor combinations involving depression, hospital-diagnosed infections, or CVD showed the strongest superadditive effects. Interactions between some risk factors were seen in only some of the studied subgroups (eg, in the 1948–57 birth cohorts and individuals with low education). Interpretation These findings reinforce the need for tailored dementia interventions building on country-specific evidence. Our findings on interactions between different risk factors are important for generating novel hypotheses on the mechanisms underlying dementia disorders and highlighting at-risk population groups for whom targeting of one risk factor could reduce the risk associated with the co-occurring factor. Funding The Alzheimer-forskningsfonden, the KID foundation, and the Danish Ministry of Health.