Metabolic Vulnerability Indices and Alzheimer's Disease Risk: A Prospective UK Biobank Study

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

This study aimed to examine associations of the metabolic vulnerability index (MVX), inflammatory vulnerability index (IVX), and metabolic malnutrition index (MMX) with incident AD in the United Kingdom Biobank (UKB).

Among 367,715 UKB participants without dementia (mean age 56.93 y, 54.3% female; 2006-2010 baseline), incident AD was ascertained through hospital and death registry linkage. Fully adjusted Cox models (model 3) constituted the prespecified primary analysis; 3 Bonferroni-corrected tests (α = 0.0167) addressed multiple comparisons. Restricted cubic splines characterized the association shape; interaction analyses examined potential effect modification by sex, age group, diabetes status, body mass index, inflammatory status, and polygenic risk.

Over 13.7 y, 2615 participants developed AD. Per 1-SD increase, MMX [hazard ratio (HR) = 1.16, 95% confidence interval (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.

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