The ε4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor for Alzheimer's disease (AD) and is associated with 25%–50% of late-onset AD. Several studies, including our own with the Australian Caucasian population, show that the AD risk associated with the APOE genotype is exerted across most populations worldwide with the exception of the Hispanic and African American populations. However, while the ε4 allele is generally recognized to play an important role in the pathogen-esis of AD, its mechanism of action remains controversial and is poorly understood. Others and we have shown in vitro that one potentially important mechanism of action involves its role in the metabolism of beta amyloid (Aβ) thought to be central to the pathogenesis of AD. We showed the ApoE ε4 isoform is deficient in binding to Aβ and clearing it from the extracellular space, an event that appears to be through binding of ApoE/Aβ complexes to LRP. Recently, we have shown in vivo that mouse apoE retards clearance from peripheral tissues such as liver and kidney of Aβ injected into the circulation. Furthermore, we show that Aβ administered peripherally does not result in uptake by the brain which is consistent with previous transgenic work for human Aβ showing that peripheral Aβ does not directly contribute to the pool of brain Aβ. Taken together with recent findings that proteins that bind Aβ in the periphery enhance its clearance from the brain together with recent findings that proteins that bind Aβ in periphery enhance its clearance from the brain, we propose that human apoE alters Aβ clearance in an isoform-specific manner in vivo such that apoE ε2 is most efficient and apoE ε4 is least efficient.