Association of Multimorbidity, Disease Clusters, and Modification by Genetic Factors With Risk of Dementia

Abstract

Importance: Individual conditions have been identified as risk factors for dementia; however, it is important to consider the role of multimorbidity, as conditions often co-occur.

Objective: To investigate whether multimorbidity is associated with incident dementia and whether associations vary by different clusters of disease and genetic risk for dementia.

Design, setting, and participants: This population-based prospective cohort study used data from the UK Biobank cohort, with baseline data collected between 2006 and 2010 and with up to 15 years of follow-up. Participants included women and men without dementia and aged at least 60 years at baseline. Medical conditions were captured as part of nurse-led verbal interviews conducted at baseline assessment centers. Data were analyzed from October 2020 to July 2022.

Exposures: The presence of at least 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 1 or 2 apolipoprotein (APOE) ε4 alleles.

Main outcomes and measures: The main outcome, incident dementia, was derived from hospital inpatient and death registry records. Associations of multimorbidity with dementia were assessed with Cox proportional hazards models.

Results: A total of 206 960 participants (mean [SD] age, 64.1 [2.9] years, 108 982 [52.7%] women) were included in the final sample, of whom 89 201 participants (43.1%) had multimorbidity. Over a mean (SD) of 11.8 (2.2) years of follow-up, 6182 participants (3.0%) developed dementia. The incidence rate was 1.87 (95% CI, 1.80-1.94) per 1000 person-years for those without multimorbidity and 3.41 (95% CI, 3.30-3.53) per 1000 person-years for those with multimorbidity. In Cox proportional hazards models adjusted for age, sex, ethnicity, education, socioeconomic status, and APOE-ε4 carrier status, multimorbidity was associated with an 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, and coronary heart disease cluster (HR, 2.20 [95% CI, 1.98-2.46]) and pain, osteoporosis, and dyspepsia cluster (HR, 2.00 [95% CI, 1.68-2.37]) in women and in the diabetes and hypertension cluster (HR, 2.24 [95% CI, 1.97-2.55]) and coronary heart disease, hypertension, and stroke cluster (HR, 1.94 [95% CI, 1.71-2.20]) in men, compared with no multimorbidity. The associations between multimorbidity and dementia were greater in those with a lower genetic risk of dementia (HR, 1.96 [95% CI, 1.81-2.11]) than in those with a higher genetic risk of dementia (HR, 1.39 [95% CI, 1.30-1.49]). Similar findings were observed when stratifying diseases clusters by genetic risk for dementia.

Conclusions and relevance: These findings suggest that multimorbidity was associated with an increased risk of dementia. The 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.

Figure 1.. Cox Proportional Hazards Models for the Association Between Multimorbidity and Incident Dementia by Different Follow-up Periods

^aIncidence rate per 1000 person-years. ^bAll models adjusted for age, ethnicity, education, socioeconomic status, and apolipoprotein ε4 status.

Figure 2.. Cox Proportional Hazards Models for the Association Between Number of Multimorbid Conditions and Incident Dementia

All models adjusted for age, ethnicity, education, socioeconomic status, and APOE-ε4 status. Dementia cases, sample size, hazard ratios, and incidence rates within each number of mulimorbidities group are presented in eTable 5 in the Supplement.

Figure 3.. Cox Proportional Hazards Models of the Interaction of Disease Clusters and Apolipoprotein (APOE) ε4 Status With Incident Dementia

CHD indicates coronary heart disease; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; NA, not applicable. ^aEach cluster was characterized by the 3 health conditions with the highest probabilities greater than 5% of contributing to that cluster, excluding conditions for which observed prevalence was equal to or less than that of the total population’s expected prevalence. ^bIncidence rate per 1000 person-years. ^cAll models adjusted for age, ethnicity, education, socioeconomic status and APOE-ε4. ^dNo multimorbidity non–APOE-ε4 carrier serves as reference group for non–APOE-ε4 clusters and ε4 carrier serves as reference group for ε4 carrier clusters.