Accelerated Biological Aging and Longitudinal Progression of Cardiometabolic Disease, Subsequent Dementia, and Death: A Multistate Analysis

Abstract

Background

The role of biological age (BA) acceleration in longitudinal disease progression from health to cardiometabolic disease (CMD), then to post-CMD dementia (including vascular dementia (VaD) and Alzheimer's disease (AD)), and finally to death remains unclear.

Methods

Using data from 284,723 UK Biobank participants, two established BA measures (Klemera-Doubal Method Biological Age [KDM-BA] and PhenoAge) were generated on the basis of baseline clinical biomarkers. Post-CMD dementia was defined as dementia that occurred after the first occurrence of CMD. Multistate analysis was constructed to examine the association between BA accelerations and longitudinal progression of post-CMD dementia. We further explored the role of two BA accelerations in CMD-specific transitions and dementia-specific transitions, respectively.

Results

Over a median follow-up of 13.7 years, 47,150 participants developed CMD, and 999 developed post-CMD dementia. Biologically older participants demonstrated robustly higher risks from healthy to CMD, then to post-CMD dementia, and finally to death. For the transition from baseline to CMD, adjusted HRs (95% CI) were 1.34 (1.32, 1.35) for each SD increase in KDM-BA acceleration and 1.19 (1.18, 1.20) for PhenoAge acceleration. For the transition from CMD to post-CMD dementia, HRs were 1.12 (1.04, 1.20) for KDM-BA acceleration and 1.10 (1.04, 1.17) for PhenoAge acceleration. Both BA accelerations were more strongly associated with the transition from CMD to post-CMD VaD than with the transition to post-CMD AD.

Conclusions

BA accelerations hold promise for identifying the disease progression of post-CMD dementia in routine clinical practice and slowing down disease progression through the interventions that slow down biological aging.