Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease

Converging evidence has identified a potential association among Alzheimer's disease, glucose metabolism, insulin activity, and memory. Notably, type 2 diabetes, which is characterized by insulin resistance, may modulate the risk of Alzheimer's disease, and patients with Alzheimer's disease may have a greater risk for glucoregulatory impairments than do healthy older adults. In animal studies, it has been shown that raising blood glucose levels acutely can facilitate memory, in part, by increasing cholinergic activity, which is greatly diminished in patients with Alzheimer's disease. Other studies have confirmed that glucose administration can facilitate memory in healthy humans and in patients with Alzheimer's disease. Interestingly, glucose effects on memory appear to be modulated by insulin sensitivity (efficiency of insulin-mediated glucose disposal). Of course, the acute effects of glucose administration should be distinguished from the effects of chronic hyperglycemia (diabetes), which has been associated with cognitive impairments, at least in older adults. The relationship of insulin and memory has been more difficult to characterize. In animals, systemic insulin administration has been associated with memory deficits, likely due, in part, to hypoglycemia that occurs when exogenous insulin is not supplemented with glucose to maintain euglycemia. In healthy adults and patients with Alzheimer's disease, raising plasma insulin levels while maintaining euglycemia can improve memory; however, raising plasma glucose while suppressing endogenous insulin secretion may not improve memory, suggesting that adequate levels of insulin and glucose are necessary for memory facilitation. Clinical studies have corroborated findings that patients with Alzheimer's disease are more likely than healthy older adults to have reduced insulin sensitivity, and further suggest that apolipoprotein E genotype may modulate the effects of insulin on glucose disposal, memory facilitation, and amyloid precursor protein processing. Collectively, these findings support an association among Alzheimer's disease, impaired glucose metabolism, and reduced insulin sensitivity.