Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 69, Issue 2, Pages 489-498Publisher
IOS PRESS
DOI: 10.3233/JAD-180578
Keywords
Alzheimer's disease; biomarkers; brain insulin resistance; extracellular vesicles; exosomes; intranasal insulin
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Funding
- Intramural research Program of the NIH, National Institute on Aging
- [P30AG049638]
- [RO1 AG027415]
- NATIONAL INSTITUTE ON AGING [ZIAAG000975] Funding Source: NIH RePORTER
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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 e4 non-carriers. Conclusion: Neuronal EV biomarkers of insulin resistance (p5312-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.
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