Insulin Metabolism in Alzheimer’s Disease Differs According to Apolipoprotein E Genotype and Gender

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)-Ε4 allele. We examined the relationship of APOE and gender to peripheral insulin action and hyperinsulinemic memory facilitation in patients with AD using a sensitive measure of insulin-mediated glucose disposal. Participants were 32 patients with AD (9 without an Ε4 allele, 23 with an Ε4 allele) and 25 healthy age-matched adults (16 without an Ε4 allele, 9 with an Ε4 allele). AD subjects without an Ε4 allele had significantly lower insulin-mediated glucose disposal rates than AD patients with an Ε4 allele (p < 0.03), or than normal adults without an Ε4 allele (p < 0.02). Female AD subjects showed lower insulin-mediated glucose disposal rates than did male AD subjects (p < 0.02). No significant interaction was observed between APOE group and gender, suggesting that these effects are independent. AD subjects without an Ε4 allele also showed significant memory facilitation in the hyperinsulinemic condition (p < 0.04), whereas the AD-Ε4 group did not. Also in the hyperinsulinemic condition, AD patients without an Ε4 allele had lower insulin levels than patients with an Ε4 allele (p < 0.02), and women with AD had lower insulin levels than did men with AD despite similar insulin infusion rates and body mass (p < 0.004). No gender or genotype effects were observed in either condition for normal subjects. These results provide in vivo evidence of differences in insulin-mediated energy metabolism between Ε4 and non-Ε4 AD, and suggest that defective insulin action may be of particular pathophysiologic significance for patients without an Ε-4 allele.