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.