Insulin-Like Growth Factor I as a Disease-Modifying Therapy in Alzheimer's Dementia
Although there is now ample consensus that the appropriate way to treat Alzheimer's dementia (AD) is through a disease-modifying therapy, this goal has not been accomplished yet. Accumulating evidence from two avenues of research now converge to suggest that late-onset AD is primarily a metabolic impairment not only affecting neurons, but brain tissue as a whole. Chronologically, the first evidence of a metabolic disturbance in AD arose from the observation of insulin dysregulation in these patients. Later, the closely related neuroprotective hormone, insulin-like growth factor I (IGF-I), that shows an intricate relationship with insulin was also associated to AD pathology. This new knowledge eventually led us to postulate a pathogenic significance of this compound derangement. That is, a combined alteration in insulin/IGF-I signalling at brain level causes AD. This proposal predicted that serum IGF-I levels in AD will vary along the course of the disease, high in initial stages, low at more advanced stages. This prediction has been confirmed by independent studies. It also predicts that inflammation will be a major determinant in progress of the disease. This remains to be shown. If this view is correct, understanding of the environmental/genetic interactions underlying insulin/IGF-I dysregulation will eventually lead to disease-modifying druggable targets. Meanwhile, the use of IGF-I in conjunction with insulin sensitizers may be a feasible, disease-modifying therapy for AD.