Insulin-like peptides signaling in Alzheimer's disease: on the road to alternative therapeutics

•Brain insulin-like peptides (ILPs) signaling is profoundly altered in Alzheimer's disease (AD) patients.•The main pathological disturbances associated to AD could result from a dysfunctional ILP system in the brain.•Targeting brain ILP resistance in AD will provide new therapeutic opportunities.

Several decades ago, the observation that Alzheimer's disease (AD) presents early disturbances in brain glucose metabolism prompted the notion of insulin dysregulation in this condition. Since then, abundant epidemiological evidence has associated AD to insulin resistance as in type 2 diabetes mellitus (T2DM). However, because the role of insulin in brain glucose handling is not clear, it cannot yet be firmly stated whether a T2DM-like condition in the brain might be cause or consequence of AD pathology. Additionally, it is becoming apparent that insulin and the closely related insulin-like peptides (i.e. IGF-I and IGF-II) modulate cognition in normal physiology, whereas robust evidence indicates central impairment of insulin/IGF-I signaling in AD patients. This may provide new leads into the pathology, even though there is still controversy on the role of these hormones in the pathogenesis of Alzheimer's dementia. At any rate, preliminary clinical trials using either intranasal insulin or IGF-I stimulating therapy show promising results. The present review summarizes major findings in the field during the last years, an intense period of research in this area.