Extracellular Vesicle Biomarkers Track Cognitive Changes Following Intranasal Insulin in Alzheimer's Disease.

BACKGROUND: Insulin resistance is implicated in Alzheimer's disease (AD), whereas intranasal insulin is an experimental treatment in clinical trials. We previously proposed insulin signaling mediators in plasma neuronal-enriched extracellular vesicles (EVs) as biomarkers of brain insulin resistance.
OBJECTIVE: We sought to demonstrate the capacity of neuronal-enriched EV biomarkers to demonstrate target engagement in response to intranasal insulin and their ability to track treatment-associated cognitive changes in AD.
METHODS: We isolated neuronal-enriched EVs from plasma samples of participants with amnestic mild cognitive impairment or probable AD involved in a 4-month duration placebo-controlled clinical trial of 20 or 40 IU intranasal insulin. We measured insulin signaling mediators as biomarkers and examined treatment-associated changes and their relationship with cognitive performance (ADAS-Cog).
RESULTS: There were no EV biomarker changes from baseline in any of the treatment groups. In participants treated with 20 IU insulin, EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) showed strong positive correlations with ADAS-Cog changes, especially in ApoE ɛ4 non-carriers.
CONCLUSION: Neuronal EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) were associated with cognitive changes in response to low dose intranasal insulin suggesting engagement of the insulin cascade in neurons of origin.

RCT Entities:   Population Interventions Outcomes