The impact of insulin resistance on cognitive impairment and cerebrospinal fluid biomarkers in Alzheimer's disease

Insulin resistance has been proposed as a modifiable risk factor for cognitive impairment and Alzheimer's disease (AD). However, its relationship with clinical and biological markers of AD remains unclear. This study investigated the associations between insulin resistance, cerebrospinal fluid (CSF) biomarkers of AD and cognitive performance in a Memory Clinic cohort. Two hundred individuals were enrolled among consecutive subjects referred for cognitive evaluation. All of them underwent neuropsychological assessments, blood sampling, and lumbar puncture for CSF collection. Insulin resistance was assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA), derived from fasting insulin and glucose levels. CSF biomarkers of amyloidopathy, tauopathy and neurodegeneration were quantified using chemiluminescent enzyme immunoassays. Participants were classified as AD or non-AD, and individuals with diabetes were excluded from the analyses. No significant differences in HOMA were observed between AD and non-AD groups, and insulin resistance was not significantly associated with CSF biomarkers of AD. However, within the AD group, individuals with dementia exhibited significantly higher insulin resistance than those with mild cognitive impairment. Across the full sample, insulin resistance was negatively correlated with global cognition. In the AD group, multiple linear regression analyses adjusted for age, sex, education, and CSF biomarkers confirmed that insulin resistance independently predicted cognitive performance. These findings suggest that insulin resistance is associated with more severe cognitive impairment in individuals within the AD continuum through mechanisms largely independent of core AD pathophysiology. Nevertheless, addressing insulin resistance may represent a promising avenue for therapeutic intervention or risk reduction in cognitive disorders.