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)epsilon E4 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 epsilon 4 allele, 23 with an epsilon 4 allele) and 25 healthy age-matched adults (16 without an epsilon 4 allele, 9 with an epsilon 4 allele). AD subjects without an epsilon 4 allele had significantly lower insulin-mediated glucose disposal rates than AD patients with an epsilon 4 allele (p < 0.03), or than normal adults without an epsilon 4 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 epsilon 4 allele also showed significant memory facilitation in the hyperinsulinemic condition (p < 0.04), whereas the AD-epsilon 4 group did not. Also in the hyperinsulinemic condition, AD patients without an epsilon 4 allele had lower insulin levels than patients with an epsilon 4 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 epsilon 4 and non-epsilon 4 AD, and suggest that defective insulin action may be of particular pathophysiologic significance for patients without an epsilon-4 allele.