Affiliations: [a] Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA
| [b] Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
Correspondence:
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Correspondence to: Dimitrios Kapogiannis, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Tel.: +1 410 350 3953; E-mail: [email protected].
Note: [1] Joint senior authors
Abstract: 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.
