Public Health.

Area of Science:

• Neuroscience
• Genetics
• Metabolic Health

Background:

• Insulin resistance (IR) is linked to cognitive decline and dementia risk.
• Polygenic risk scores (PRS) can identify genetic predisposition to IR.
• Understanding the genetic liability to IR's impact on memory is crucial for dementia prevention.

Purpose of the Study:

• To investigate the association between genetic liability to IR and memory performance.
• To examine cross-sectional and longitudinal relationships between IR genetic risk and memory.
• To explore how comorbidities and APOE genotype modify this association.

Main Methods:

• A polygenic risk score (PRS) for IR was constructed using TG:HDL-C ratio from genome-wide association study data.
• The PRS was applied to the National Alzheimer's Coordinating Center (NACC) cohort.
• Linear regression and mixed-effects models analyzed baseline and longitudinal memory, adjusting for covariates and performing sensitivity analyses.

Main Results:

• Higher genetic risk for IR (TG:HDL-C PRS) was associated with better baseline memory.
• Increased genetic risk for IR correlated with slower longitudinal memory decline.
• Associations were modified by comorbidities and APOE-ɛ4/ɛ2 non-carrier status, with reduced effect sizes when comorbidities were excluded.

Conclusions:

• Genetic liability to IR, indicated by TG:HDL-C PRS, shows a modest but significant association with better memory and slower decline.
• Comorbidities and APOE genotype significantly modify the relationship between IR genetic risk and memory.
• Further research with larger cohorts is needed to elucidate the complex interplay of IR genetics, metabolism, and cognitive health.