The ε4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD), perhaps through effects on amyloid-β (Aβ) metabolism. Detailed analyses of various Aβ parameters in aging APPV717F+/-transgenic mice expressing mouse apoE, no apoE, or human apoE2, apoE3, or apoE4 demonstrate that apoE facilitates, but is not required for, Aβ fibril formation in vivo. Human apoE isoforms markedly delayed Aβ deposition relative to mouse apoE, with apoE2 (and apoE3 to a lesser extent) having a prolonged ability to prevent Aβ from converting into fibrillar forms. Isoform-specific effects of human apoE on Aβ levels and neuritic plaque formation mimicked that observed in AD (E4 > E3 > E2). Importantly, observation of an apoE-dependent decrease in percent soluble Aβ and enrichment of Aβ in membrane microdomains prior to Aβ deposition indicates that apoE influences Aβ metabolism early in the amyloidogenic process and provides a possible novel mechanism by which apoE affects AD pathogenesis.