Thus far, we have examined the relationship between insulin and normal memory, and now we turn to the relationship between insulin and dementia. As we have seen, diabetes increases the risk for both cognitive decline and dementia. It is important to keep in mind that T2DM represents both abnormal glycemic regulation and abnormal insulin activity. This section will examine the relationship between Alzheimer's disease, the most common form of dementia among older adults, and insulin abnormalities. First, we turn to a brief discussion on Alzheimer's disease. Then, we will turn to the discussion on insulin resistance and Alzheimer's disease.
Dementia is a pathological condition characterized by deficits in memory, another area of cognitive functioning, and social or occupational functioning. The most common form of dementia among older adults is Alzheimer's disease. The most prominent symptom of Alzheimer's disease is a loss of declarative memory, which begins insidiously and invariably progresses, usually until the person with Alzheimer's disease has no memory for self or others. Structural brain imaging frequently shows progressive atrophy of the hippocampus, a structure known to play an essential role in the formation of declarative memory (3). Furthermore, functional imaging has revealed a decrease in glucose metabolism in the hippocampus, superior and middle temporal gyri, and the cingulate gyrus (48). Other hallmark pathologies of Alzheimer's disease are the formation of amyloid plaques, neurofibrillary tangles, generalized cerebral atrophy, and neurotransmitter changes.
Insulin and Apolipoprotein E (APOE) Genotype
The most important genetic risk factor for Alzheimer's disease is apolipoprotein E (APOE), which likely functions to shift the age of onset of Alzheimer's disease by several years. There are three isoforms of the APOE gene; APOE s3, which is the most common isoform and is considered to have a relative risk of 1.0, APOE s2, which is the least common and is thought to convey a reduced risk for Alzheimer's disease, and APOE s4, which dose-dependently increases the risk for Alzheimer's disease (49). Interestingly, this genotype may modulate the relationship between metabolic abnormalities and Alzheimer's disease. For example, we have previously reported that APOE genotype distinguished groups of Alzheimer's patients on several metabolic measures, including insulin sensitivity (assessed by the rate of glucose disposal during a hyperinsulinemic-euglycemic clamp procedure), plasma insulin concentrations, and the ratio of insulin in spinal fluid to insulin in plasma (31-34, 50). Furthermore, we have observed that APOE differentiated groups of patients with Alzheimer's disease regarding the optimal insulin dose producing facilitation of memory and attention (31, 51). Finally, possession of the s4 allele influenced the insulin-related processing of the amyloid precursor protein from which the A| peptide is derived. Interestingly, patients possessing the s4 allele were more insulin sensitive on metabolic measures and were more sensitive to insulin dose effects than were their counterparts who did not possess the s4 allele. These observations raise the intriguing possibility that treatment for Alzheimer's disease may need to consider this genetic factor.
In recent years, a number of investigators have reported insulin defects in Alzheimer's disease. Notably, patients with Alzheimer's disease may have reduced insulin-mediated glucose disposal, indicative of insulin resistance, or may be at risk for abnormal glucose metabolism (11, 52). Converging evidence is consistent with the hypothesis that brain insulin signaling is abnormal in patients with Alzheimer's disease (29). De la Monte and other investigators have reported reductions in the following components of the insulin signaling pathway: tyrosine kinase activity, insulin concentration, IRS mRNA, IRS-associated phosphatidylinositol 3-kinase, and activated phosphor-Akt (24, 53, 54). These abnormalities are sufficient to influence energy production, oxidative stress, cell survival, GSK-3| activation, and advanced glycation of proteins (29). De la Monte and colleagues have proposed that these insulin signaling abnormalities are so profound that they constitute "type 3 diabetes" or brain insulin resistance associated with Alzheimer's disease (25). When they modeled type 3 diabetes in rodents, using streptozotocin administration, they found changes in the brain similar to those found in patients with Alzheimer's disease: atrophy; increased levels of activated GSK-3|, phospho-tau, and |-amyloid (A|); and decreased expression of a number of genes (55).
The principal constituent of neuritic plaques is |-amyloid, primarily the more toxic species, A|42. A| is produced in the brain, where it may remain as amyloid deposits or from where it may be cleared by degradation or transported across the blood-brain barrier into the peripheral sink (56). Insulin plays several roles in regulating levels of | -amyloid including promoting the release of A| from the intracellular compartment and accelerating A| trafficking to the plasma membrane (57). These observations suggest that insulin potentially may increase A| levels. Conversely, A| degradation may depend in part on insulin . Both A| and insulin are degraded by insulin-degrading enzyme, which is highly expressed in brain and liver (58-60). Notably, insulin-degrading enzyme has a preferential affinity for insulin over A| . Consequently, it is likely that excess insulin in the brain could result in decreased A| degradation. Consistent with these observations, increasing insulin levels should result in increased A| levels. Indeed, when we administered insulin to healthy older adults and maintained euglycemia, we found that both A| and insulin levels were increased in spinal fluid and that reduced memory facilitation was associated with increased A| levels (61). Furthermore, body mass index, a measure that is highly related to insulin resistance, was associated with plasma Aß42 levels, such that body mass index rose as plasma Aß levels rose (62).
Inflammation appears to play a crucial role in Alzheimer's disease. It has been reported that patients with Alzheimer's disease have elevated levels of interleukin 6 (IL-6) and F-2 isoprostane, a marker of lipid peroxidation, in spinal fluid and tumor necrosis factor-a (TNF-a) in spinal fluid and plasma (63-65). Several observations implicate insulin as a regulator of inflammation in patients with Alzheimer's disease. First, insulin has dual competing effects on inflammation in the periphery: whereas low insulin doses are associated with an anti-inflammatory response (66), chronic hyperinsulinemia is associated with a proinflammatory response (67), and exogenous insulin can increase the proinflammatory reaction to an endotoxin such as lipopolysac-charide (68). Second, moderate doses of systemically administered insulin can induce a rapid proinflammatory response. For 16 healthy older adults, we raised plasma insulin levels to about 80 ^(mu)U/ml while maintaining normal blood sugar levels. After 90 min of insulin infusion, lumbar spinal fluid was acquired. Relative to saline, insulin induced marked increases in spinal fluid concentrations of IL-1a, IL-1ß, IL-6, TNF-a, and F-2 isoprostane. Third, a reciprocal relationship exists between Aß and inflammation. On the one hand, soluble Aß oligomers induce a rapid inflammatory response in vitro, which leads to increased levels of the proinflammatory cytokines IL-1ß and IL-6 (69). Aß also induces glial activation, cytokine gene expression, and expression of COX-2 (70). On the other hand, the production of Aß from the amyloid precursor protein (APP) is governed, in part, by IL-1ß and IL-6, which act to increase concentrations of Aß42, the most toxic Aß isoform (71, 72). The net result is a "cytokine cycle," leading to increased Aß and IL-1ß/IL-6.
Insulin, Obesity, and Free Fatty Acids (FFA)
Obesity is a major risk factor for metabolic (or insulin resistance) syndrome. As body mass index (BMI, a weight-to-height ratio) increases, the risk for hyperinsulinemia, hyperglycemia, hypertension, and dyslipidemia also increases. It has recently been reported that BMI can modulate plasma concentrations of A|42, the longer and more toxic species of the A| family. In a group of healthy adults, A|42 was strongly correlated with both BMI (r = 0.55) and fat mass (r = 0.60) (62). Consistent with these data, longitudinal data support the notion that a higher BMI is predictive of incident Alzheimer's disease in Swedish adults ranging in age from 70 to
88 (73). Finally, we have reported that BMI modulated the relationship between insulin-induced memory facilitation and plasma levels of A| 42 (r = 0.49) (61).
FFAs likely provide a connection between obesity and insulin resistance. Elevated FFAs are common in people with obesity or insulin resistance, and normalization of FFA levels typically leads to a dramatic improvement in insulin sensitivity (74). Furthermore, high fasting FFA levels are associated with progression to diabetes (75, 76). FFAs are also associated with inflammation. For example, TNF-a, a proinflammatory cytokine expressed in adipocytes, has a role in regulating glucose uptake that may be mediated in part by FFAs. Insulin resistance is associated with overexpression of TNF-a in adipocytes, and reducing TNF-a levels has a beneficial effect on insulin resistance (77). FFAs are also expressed in the brain where they may play several important roles. Following head injury, brain levels of FFAs rise, suggesting that FFAs may be part of the body's normal response to brain trauma (78). Additionally, FFAs inhibit mitochondrial respiration, suggesting that FFAs play a role in energy metabolism at the subcellular level (79). This has direct relevance to Alzheimer's disease, a condition in which cerebral glucose metabolism is reduced. Also of direct relevance to Alzheimer's disease, insulin-degrading enzyme is inhibited by FFAs. As previously noted, insulin-degrading enzyme degrades both insulin and A|. Therefore, it is possible that high levels of FFAs would lead to reduced degradation of A| .
Thus far, we have reviewed evidence suggesting that there is a relationship among glucose, insulin, and memory, that impaired glucose metabolism and insulin action are associated with changes in cognitive functioning, and that insulin abnormalities may contribute to the pathophysiology and cognitive symptoms of Alzheimer's disease, the most common form of dementia in older adults. We have also considered mechanisms that may account for the relationship between insulin and Alzheimer's disease. In the next section, we will discuss several potential treatments for Alzheimer's disease based on improving insulin action in the periphery and the brain.
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