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.