Multimorbidity and risk of incident dementia: role of disease clusters and genetic risk for dementia in a cohort of 206,960 participants

Abstract ImportanceIndividual conditions have been identified as risk factors for dementia, however, it is important to consider the role of multimorbidity as conditions often co-occur. ObjectiveTo investigate whether multimorbidity is associated with incident dementia, and whether associations vary by different clusters of disease, and genetic risk for dementia. DesignA population-based prospective study. SettingThe UK Biobank cohort. Participants206,960 dementia-free women and men aged ≥60 years old at baseline Exposures: Medical conditions were captured as part of a nurse-led verbal interview conducted at assessment centres. The presence of ≥2 long-term conditions from a preselected list of 42 conditions was used to define multimorbidity. High genetic risk for dementia was based on presence of one or two Apolipoprotein (APOE) ε4 alleles. Main outcomeIncident dementia was derived from hospital inpatient and death registry records. Results89,201 (43%) participants had multimorbidity. Over a mean of 11.8 years (standard deviation=2.2), 6,182 participants developed dementia. The incidence rate per 1,000 person years was 1.87 (95% Confidence Interval [CI] 1.80-1.94) and 3.41 (95% CI 3.30-3.53) for those without and with multimorbidity, respectively. In Cox-proportional-hazards models adjusted for age, sex, ethnicity, education, socioeconomic status and APOE-ε4 carrier status, multimorbidity was associated with a 63% increased risk of incident dementia (Hazard Ratio [HR]=1.63, 95% CI 1.55-1.71). The highest dementia risk was observed for the hypertension/diabetes/coronary heart disease (HR=2.20, 95% CI 1.98-2.46) and pain/osteoporosis/dyspepsia (HR=2.00, 95% CI 1.68-2.37) clusters in females and diabetes/hypertension (HR=2.24, 95% CI 1.97-2.55) and coronary heart disease/hypertension/stroke clusters (HR=1.94, 95% CI 1.71-2.20) in males, compared to no multimorbidity. The relative associations were stronger in those with a lower genetic risk of dementia, but the absolute difference in risk between absence and presence of multimorbidity was greater in those with a higher genetic risk for dementia. Conclusions and RelevanceMultimorbidity was strongly associated with an increased risk of dementia. The strength of associations varied by clusters of disease and genetic risk for dementia. These findings could help with the identification of individuals at high risk of dementia as well as the development of targeted interventions to reduce or delay dementia incidence.