Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype

In previous studies, adults with Alzheimer's disease (AD) showed memory enhancement when plasma insulin levels were raised to 85 muU/ml, whereas normal adults' memory was unchanged. Degree of memory enhancement was also related to apolipoprotein E (apoE) genotype status for AD patients. Response differences between normal and AD groups could reflect dose-response differences for insulin. To examine this question, 22 adults with AD and 15 normal adults received five doses of insulin on separate days in counterbalanced order, resulting in five plasma insulin levels (10, 25 35, 85 and 135 muU/ml), while plasma glucose levels of similar to100 mg/dl were maintained. Cognitive performance and plasma APP levels were measured after 120 min of infusion. Relative to baseline, AD patients who were not apoE-epsilon4 homozygotes had improved memory at higher insulin levels of 35 and 85 muU/ml, whereas normal adults and AD patients who were epsilon4 homozygotes showed improved memory at insulin levels of 25 muU/ml. Normal adults' memory was also improved at insulin levels of 85 muU/ml. Plasma APP was lowered for adults with AD without the epsilon4 allele at higher levels (85 muU/ml) than for normal adults and epsilon4 homozygotes, who showed decreased APP at the 35 muU/ml level. AD patients with a single epsilon4 allele showed a different pattern of insulin effects on APP than did other subjects. In general, few effects of insulin were seen at the highest dose for any subject group. These results support a role for insulin in normal memory and APP modulation that follows a curvilinear response pattern, and suggest that AD patients who are not epsilon4 homozygotes have reduced sensitivity to insulin that may interfere with such modulation. (C) 2003 Elsevier Science Ltd. All rights reserved.