Summary

Background

Individual cardiometabolic disorders and genetic factors are associated with an increased risk of dementia; however, the relationship between dementia and cardiometabolic multimorbidity is unclear. We investigated whether cardiometabolic multimorbidity increases the risk of dementia, regardless of genetic risk, and examined associated structural brain changes.

Method

We examined genetic and health data from 203,038 UK Biobank participants of European ancestry, aged 60 years or older without dementia at baseline (2006-10) and followed up to 31 March 2021 in England and Scotland and 28 February 2018 in Wales, as well as brain structural data. in the nested image subsample of 12,236 participants.

A cardiometabolic multimorbidity index consisting of stroke, diabetes, and myocardial infarction (one point each) and a polygenic risk score for dementia (with low, medium, and high risk groups) was calculated for each participant. The primary outcome measures were dementia from each incident cause and brain structural metrics.

Results

The risk of dementia associated with high cardiometabolic multimorbidity is three times higher than that of high genetic risk (hazard ratio [HR] 5.55, 95% CI 3.39-9.08, p<0.0001 and 1.68, 1 53-1 84, p<0.0001, respectively).

Participants with a high genetic risk and a cardiometabolic multimorbidity index of two or more had higher risk developed dementia (HR 5.74, 95% CI 4.26-7.74, p<0.00001), compared with those with a low genetic risk and no cardiometabolic condition.

Basically, we did not find interaction between cardiometabolic multimorbidity and polygenic risk (p=0.18). Cardiometabolic multimorbidity was independently associated with more extensive and pervasive brain structural changes, including lower hippocampal volume (F2, 12 110 = 10 70; p < 0.0001) and total gray matter volume (F2, 12 236 = 55 65 ; p<0.001 ).

Interpretation

It cardiometabolic multimorbidity independently associated with dementia risk and large differences in brain imaging to a greater extent than genetic risk. Targeting cardiometabolic multimorbidity may help reduce the risk of dementia, regardless of genetic risk.