Metabolic Vulnerability Indices and Alzheimer's Disease Risk: A Prospective Analysis of the UK Biobank Cohort.

Background

Metabolic dysfunction is implicated in Alzheimer's disease (AD) pathogenesis. Branched-chain amino acids (BCAAs) have been prospectively linked to dementia risk, yet prospective associations of composite metabolic vulnerability indices with incident AD remain untested.

Objective

To examine associations of the Metabolic Vulnerability Index (MVX), Inflammatory Vulnerability Index (IVX), and Metabolic Malnutrition Index (MMX) with incident AD in the UK Biobank.

Methods

Among 367,715 dementia-free UK Biobank participants (mean age 56.93 years, 54.3% female; 2006-2010 baseline), incident AD was ascertained through hospital and death registry linkage. Fully adjusted Cox models (Model 3) constituted the pre-specified primary analysis; three Bonferroni-corrected tests (α = 0.0167) addressed multiple comparisons. Restricted cubic splines characterized association shape; interaction analyses examined potential effect modification by sex, age group, diabetes status, BMI, inflammatory status, and polygenic risk.

Results

Over 13.7 years, 2,615 participants developed AD. Per 1-SD increase, MMX (HR = 1.16, 95% CI: 1.12-1.21, p = 4.93×10-13) and MVX (HR = 1.12, 95% CI: 1.07-1.17, p = 3.72×10-6) were each associated with higher AD risk, both meeting the Bonferroni-corrected threshold; IVX showed no association (p = 0.108). Associations were approximately linear and monotonically increasing. Sex-specific associations were observed for MMX (stronger in males, p-interaction = 0.004) and MVX (stronger in females, p-interaction = 0.003). Sensitivity analyses confirmed robustness.

Conclusion

MMX and MVX are independently associated with incident AD, supporting the clinical relevance of metabolic health monitoring in neurodegeneration risk stratification.