Insulin resistance, cognition and Alzheimer's disease biomarkers: evidence that CSF Aβ42 moderates the association between insulin resistance and increased CSF tau levels

Mounting evidence implicates insulin resistance (IR) with reduced cognition, increased dementia risk and changes in Alzheimer's disease biomarkers. It's unclear how, and at what stage IR has the greatest impact on Alzheimer's disease biomarker progression indicative of cognitive decline. Exploration of potential factors influencing this relationship continue. We have previously reported IR to be associated with cognitive function, and increased CSF tau in a cognitively unimpaired cohort. Now, we aimed to determine if CSF total (t-tau) or phosphorylated tau (p-tau) mediated the relationship between HOMA-IR and cognition, and explore sex or amyloid-β (Aβ) biomarkers as moderators of this relationship. Mediation analysis demonstrated that CSF tau does not directly influence the association between HOMA-IR and cognition. Moderation analysis revealed CSF Aβ42 moderates the relationships between HOMA-IR and CSF tau. The combination of lower CSF Aβ42 and higher HOMA-IR was associated with increases in CSF tau. The CSF Aβ42 moderation finding has potential to be considered when assessing type 2 diabetic risk for tau pathology and cognitive decline.