Abstract
INTRODUCTION: Liver-metabolic stress and apolipoprotein E (APOE) ε4 are implicated in late-life cognitive vulnerability, yet how hepatic-metabolic indices relate to cognition and amyloid burden and whether these associations vary by APOE ε4 allele dose remains unclear. We examined liver-metabolic indices in relation to cognition and amyloid PET SUVR and tested effect modification by APOE ε4. METHODS: We analyzed baseline data from the Dementia Platform Korea Trial-Ready Registry (DPK-TRR). Primary multivariable analyses used complete cases for outcomes and covariates (n = 507); amyloid PET analyses used the PET subset (n = 496). Exposures included the triglyceride-glucose (TyG) index, AST/ALT ratio, and Fibrosis-4 (FIB-4) stage (low/intermediate/high). APOE ε4 was modeled as allele dose (0/1/2). Multivariable linear regression evaluated associations with global cognition (MMSE), selected domain outcomes, and amyloid PET SUVR, including FIB-4 stage × APOE ε4 dose interaction terms, adjusted for age, sex, education, hypertension, diabetes, and dyslipidemia. RESULTS: Higher TyG index and AST/ALT ratio were associated with lower MMSE scores (TyG: β = -1.13, 95% CI - 2.11 to -0.16; p = 0.022; AST/ALT: β = -1.40, 95% CI - 2.10 to -0.39; p = 0.007) and with memory performance on CERAD delayed recall (TyG: β = -0.29, 95% CI - 0.52 to -0.06; p = 0.012), whereas neither marker showed a clear association with amyloid PET SUVR. The association between FIB-4 stage and cognition differed by APOE ε4, showing a cross-over pattern across fibrosis stages: APOE ε4-associated differences were attenuated and reversed at intermediate/high FIB-4 compared with low FIB-4. In the amyloid PET subset, APOE ε4 group differences in SUVR were not prominent at low FIB-4, but tended to diverge at high FIB-4 with higher SUVR in groups with greater ε4 burden. CONCLUSION: Routine liver-metabolic indices were associated with cognitive performance, while FIB-4 stage showed effect modification by APOE ε4 in relation to both cognition and amyloid PET SUVR. These findings support heterogeneity in liver-metabolic and genetic contributions to late-life cognitive vulnerability in a dementia trial-ready registry and motivate longitudinal studies to clarify temporal relationships.