Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study

Tai, X. Y., Veldsman, M., Lyall, D. M. , Littlejohns, T. J., Langa, K. M., Husain, M., Ranson, J. and Llewellyn, D. J. (2022) Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study. Lancet Healthy Longevity, 3(6), e428-e436. (doi: 10.1016/S2666-7568(22)00117-9) (PMID:35711612) (PMCID:PMC9184258)

Abstract

Background: Individual cardiometabolic disorders and genetic factors are associated with an increased dementia risk; 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 for associated brain structural changes. Methods: We examined health and genetic data from 203 038 UK Biobank participants of European ancestry, aged 60 years or older without dementia at baseline assessment (2006–10) and followed up until March 31, 2021, in England and Scotland and Feb 28, 2018, in Wales, as well as brain structural data in a nested imaging subsample of 12 236 participants. A cardiometabolic multimorbidity index comprising stroke, diabetes, and myocardial infarction (one point for each), and a polygenic risk score for dementia (with low, intermediate, and high risk groups) were calculated for each participant. The main outcome measures were incident all-cause dementia and brain structural metrics. Findings: The dementia risk associated with high cardiometabolic multimorbidity was three times greater than that associated with 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 both a high genetic risk and a cardiometabolic multimorbidity index of two or greater had an increased risk of developing dementia (HR 5·74, 95% CI 4·26–7·74, p<0·0001), compared with those with a low genetic risk and no cardiometabolic conditions. Crucially, we found no interaction between cardiometabolic multimorbidity and polygenic risk (p=0·18). Cardiometabolic multimorbidity was independently associated with more extensive, widespread brain structural changes including lower hippocampal volume (F2, 12 110 = 10·70; p<0·0001) and total grey matter volume (F2, 12 236 = 55·65; p<0·0001). Interpretation: Cardiometabolic multimorbidity was independently associated with the risk of dementia and extensive brain imaging differences to a greater extent than was genetic risk. Targeting cardiometabolic multimorbidity might help to reduce the risk of dementia, regardless of genetic risk.

• Item Type: Articles
• Additional Information: This work was funded by the Wellcome Trust (Wellcome Trust PhD clinical fellowship to XYT and Wellcome Trust Principal Research Fellowship to MH), Alzheimer’s Research UK (to JR and DJL), Alan Turing Institute/Engineering and Physical Sciences Research Council (grant number EP/N510129/1 to JR and DJL), the National Institute for Health Research Applied Research Collaboration South West Peninsula (to DJL), National Health and Medical Research Council (to DJL), JP Moulton Foundation (to DJL), and the National Institute on Aging/ National Institutes of Health (grant RF1AG055654 to DJL and R01 AG053972, P30 AG066582, and P30 AG024824 to KML).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lyall, Dr Donald
• Authors: Tai, X. Y., Veldsman, M., Lyall, D. M., Littlejohns, T. J., Langa, K. M., Husain, M., Ranson, J., and Llewellyn, D. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
• Journal Name: Lancet Healthy Longevity
• Publisher: Lancet Publishing Group
• ISSN: 2666-7568
• Published Online: 09 June 2022
• Copyright Holders: Copyright © 2022 The Author(s)
• First Published: First published in Lancet Healthy Longevity 3(6): e428-e436
• Publisher Policy: Reproduced under a Creative Commons License