Insulin resistance (TyG index) and body mass index as metabolic biomarker combined with ApoE genotype to diagnose Alzheimer’s disease

Background: Growing evidence suggests that both ApoE genotype and metabolic disturbances including insulin resistance (IR) and obesity constitute risk factors for Alzheimer's disease (AD). However, large-scale studies investigating whether ApoE genotype interacts with metabolic abnormalities to indirectly impair cognitive function in AD remain scarce. Objective: This cross-sectional study aimed to explore the associations between ApoE genotype, metabolic disturbances [IR assessed by triglyceride-glucose (TyG) index and body mass index (BMI)], and cognitive function in AD patients. Methods: We analyzed 1,162 clinically diagnosed probable AD patients from the Cognitive Impairment Clinic at Tianjin Huanhu Hospital. Participants were categorized by ApoE ε4 carrier status. Metabolic parameters were evaluated using the TyG index and BMI. Mediation effect models were employed to assess the relationships between ApoE genotype, metabolic indices, and cognitive function. Results: = 0.009). Mediation analysis revealed that ApoE ε4 exerted 73.4% of its negative effect on cognition through direct pathways, while 9.7 and 16.9% were mediated through BMI reduction and TyG elevation, respectively. Conclusion: ApoE ε4 carriers demonstrate a distinct metabolic profile characterized by lower BMI and elevated TyG index, associated with poorer cognitive performance. Our findings suggest that ApoE ε4 may indirectly influence AD cognition through metabolic pathways, highlighting early interventions targeting ApoE-related metabolic dysregulation as potential strategies to delay AD progression.