In previous studies, adults with Alzheimer's disease (AD) showed memory enhancement when plasma insulin levels were raised to 85 microU/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 microU/ml), while plasma glucose levels of ~100 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- epsilon 4 homozygotes had improved memory at higher insulin levels of 35 and 85 microuU/ml, whereas normal adults and AD patients who were epsilon 4 homozygotes showed improved memory at insulin levels of 25 microU/ml. Normal adults' memory was also improved at insulin levels of 85 microU/ml. Plasma APP was lowered for adults with AD without the epsilon 4 allele at higher levels (85 microU/ml) than for normal adults and epsilon 4 homozygotes, who showed decreased APP at the 35 microU/ml level. AD patients with a single epsilon 4 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 epsilon 4 homozygotes have reduced sensitivity to insulin that may interfere with such modulation.