Insulin Effects on Glucose Metabolism, Memory, and Plasma Amyloid Precursor Protein in Alzheimer's Disease Differ According to Apolipoprotein‐E Genotype

Abstract

Higher fasting plasma insulin levels and reduced CSF-to-plasma insulin ratios, suggestive of insulin resistance, have been observed in patients with Alzheimer's disease (AD) who do not possess an apolipoprotein E (ApoE)-epsilon 4 allele. Insulin has also been implicated in processing of beta-amyloid and amyloid precursor protein (APP). We examined the effects of intravenous insulin administration while maintaining euglycemia on insulin-mediated glucose disposal, memory, and plasma APP in patients with AD and normal adults of varying ApoE genotypes. AD subjects without an epsilon 4 allele had significantly lower insulin-mediated glucose disposal rates than did AD patients with an epsilon 4 allele (p < 0.03) or than did normal adults without an epsilon 4 allele (p < 0.02). AD subjects without an epsilon 4 allele also showed significant memory facilitation with insulin administration (p < 0.04), whereas the AD-epsilon 4 group did not. Insulin reduced APP levels for AD patients without an ApoE epsilon 4 allele, but raised APP for AD patients with an ApoE epsilon H4 allele These results document ApoE-related differences in insulin metabolism in AD that may relate to disease pathogenesis.

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

“…210 It is noteworthy that the hippocampus is rich in insulin receptors and that insulin may also have a role in memory function, an effect mediated by APOE genotype. [211][212][213][214][215] There is increased evidence supporting a role for insulin in modulating the inflammatory response, an effect which appears to be age dependent and exacerbated with overweight and obesity (reviewed in Watson and Craft 216 and Craft 217 ). Thus insulin levels may play a pivotal role in AD pathogenesis through altering cognitive function, stimulation of inflammatory processes and modulation of the clearance and degradation of Ab through multiple pathways.…”

Ketone Bodies as a Therapeutic for Alzheimer's Disease

“…57 In a follow-up study of 31 subjects with mild to moderate probable AD, E4(Ϫ) subjects were found to have significantly lower glucose disposal rates. 55 High-fasting insulin and low-glucose disposal rates both suggest that E4(Ϫ) subjects are insulin resistant, and correcting this insulin resistant state by administration of insulin either systemically, 55 nasally, 54 or by use of the insulin sensitizing agent rosglitazone 57 may explain the beneficial effects seen in these studies.…”

“…Interestingly, APOE4 effects have been noted in other studies targeting the insulin pathway as a treatment for AD. In a series of studies, Craft et al 55 found that E4(Ϫ) subjects rapidly responded to treatment with glucose and insulin, and when exposed to nasal insulin. 56 E4 effects were also seen in a larger study with the insulin sensitizing agent rosglitazone.…”

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

“…In epidemiologic studies, only E4 non-carriers showed a relation between CSF Ab and the CSF to plasma ratio for glucose, 66 and only this group showed memory improvement and a reduction in plasma APP in response to an insulin infusion; E4 carriers had no changes in memory and their plasma APP increased in response to insulin. 71 We recently published that while E4 non-carrier adults with normal cognition showed an increase in plasma Ab42 after a high-fat meal compared to a high carbohydrate meal, those who had mild cognitive impairment, and those who were E4 carriers, demonstrated higher plasma Ab after the high carbohydrate meal. 72 We speculate that individuals at risk for AD may have a different relation between diet, fat, and amyloid regulation (Figure 1(c)).…”