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)‐ɛ4 allele. Insulin has also been implicated in processing of β‐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 ɛ4 allele had significantly lower insulin‐mediated glucose disposal rates than did AD patients with an ɛ4 allele (p < 0.03) or than did normal adults without an ɛ4 allele (p < 0.02). AD subjects without an ɛ4 allele also showed significant memory facilitation with insulin administration (p < 0.04), whereas the AD‐ɛ4 group did not. Insulin reduced APP levels for AD patients without an ApoE ɛ4 allele, but raised APP for AD patients with an ApoE ɛH4 allele These results document ApoE‐related differences in insulin metabolism in AD that may relate to disease pathogenesis.