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Original Contribution: Cristina Geroldi; Giovanni B. Frisoni; Giuseppe Paolisso; Stefania Bandinelli; Marco Lamponi; Angela Marie Abbatecola; Orazio Zanetti; Jack M. Guralnik; Luigi Ferrucci Insulin Resistance in Cognitive Impairment: The InCHIANTI Study Arch Neurol 2005; 62: 1067-1072 [Abstract] [Full text] [PDF]

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Insulin Resistance and Alzheimer's disease

Steven R Brenner   (26 August 2005)

Insulin Resistance and Alzheimer's disease 26 August 2005
Steven R Brenner, MD Dept. Neurology, St. Louis VA Medical Center and Dept. Neurology St. Louis University Send reply to journal: Re: Insulin Resistance and Alzheimer's disease SBren20979{at}aol.com Steven R Brenner	I read with interest the article by Geroldi and colleagues (1) regarding insulin resistance (IR) and cognitive impairment. The findings of cognitive impairment with subcortical features including parkinsonism, and dysexecutive features on the Mini-Mental State Examination, could be due to primary neuronal degeneration or injury rather than subcortical vascular damage. Primary neuronal pathology such as Alzheimer disease (AD) could be implicated. A review of the literature indicates 2 problems, related to impaired insulin signaling in AD, the cerebral microvasculature and central nervous system neuronal function (2). Insulin is neurotrophic and supports both neuronal viability and synaptic formation, and impaired insulin signaling would lead to reduced neuronal viability and loss of synapses (2). Synaptic loss is prevalent in AD. Hyperinsulinemia is associated with a higher risk of AD; the risk of AD was found to double in a study of patients with hyperinsulinemia (3). There are extensive abnormalities in insulin and insulin-like growth factor (IGF) type I and II signaling mechanisms in patients with AD, and expression of corresponding growth factors are also markedly reduced and are associated with reduced levels of insulin receptor substrate as well (4). Insulin and IGF I and II are all expressed in the brain but AD is associated with marked reductions in insulin and IGF mRNA expression, and downregulation of their receptors (4). Insulin and IGF signaling abnormalities in the brain in AD indicate a complex disease process that appears to involve a neuroendocrine disorder with similarities to diabetes but unique features, such as failure of endogenous brain insulin production and insulin receptor deficiency. The cognitively impaired patients in the study with subcortical features may indicate primary neuronal dysfunction rather than subcortical vascular damage. 1. Geroldi C, Frisoni B, Paolisso G, et al. Insulin resistance in cognitive impairment: The InCHIANTI Study. Arch Neurol. 2005;62;1067-1072. 2. de la Monte S, Wands J. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimers Dis. 2005;7:45-61. 3. Luichsinger J, Tang M, Shea S, et al. Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004;63:1187-1192. 4. Steen E, Terry B, Rivera E, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7:63-80.