One suggested explanation for the association between high plasma levels of cholesterol and AD is that the impermeability of the bloodbrain barrier might be compromised in individuals with AD so that cholesterol can be transported into the brain from the plasma. However, more recent studies have shown that the levels of plant sterols in the brains of individuals with AD are not significantly different from those in nonAD controls, suggesting that the bloodbrain barrier remains intact in AD. In support of the idea that high levels of plasma cholesterol contribute to AD, several studies have suggested that statins, some of which can cross the bloodbrain barrier and are widely used cholesterollowering drugs, protect against AD. However, randomized doubleblind placebocontrolled studies have shown no beneficial effect of statins on the progression of symptoms in individuals with AD despite significantly lowering plasma cholesterol. Clearly, additional studies are required to determine whether high plasma cholesterol directly contributes to the onset and progression of AD. One possible mechanism underlying the proposed neuroprotection against AD by statins might be attributable to the antiinflammatory andor antioxidant properties of the statins, rather than directly to their cholesterollowering effects. Thus, the idea that statins are beneficial in AD remains controversial.ApoE mice exhibit impaired clearance of degenerating nerves, as well as learning defects, although nerve regeneration appears to be normal, APOE is secreted by astrocytes and generates cholesterolcarrying lipoproteins that are delivered to, and endocytosed by, neurons.Low levels of APOE in the brain correlate with an increased risk of AD, but whether or not the cholesterolcarrying function of APOE is involved in AD remains unclear, as discussed above.Moreover, this agonist enhanced A degradation and markedly reduced A plaque area.Remarkably, bexarotene also rapidly improved memory and cognition in the AD mice.Importantly, none of these beneficial effects occurred in mice that lacked APOE.Thus, the benefits of bexarotene in AD mice were attributed to the increased amount of APOE in the brain and the role of APOE in stimulating A degradation. However, in contrast to this report, another recent study has suggested that reducing rather than increasing APOE levels reduces the amount of A in the brain. Thus, whether or not the demonstrated benefit of bexarotene in mice can be translated into a treatment for humans with AD remains to be determined, particularly because mice express only one isoform of APOE, whereas humans express three common, alternative APOE isoforms. The three human APOE isoforms differ from each other in only a single amino acid.The most common isoform allele is APOE, whereas only of the population carries the APOE allele.Importantly, inheritance of the APOE allele is the strongest known genetic risk factor for the development of lateonset AD. Thus, individuals who have a single copy of the APOE allele have four times the likelihood of developing AD compared with carriers of the APOE allele, whereas inheritance of two APOE alleles increases the risk of developing AD by to fold. In contrast, inheritance of the APOE allele seems to protect against AD. Although the association between the APOE isoform and the predisposition of individuals to AD is well established, the reason why APOE is a risk factor for AD is still not clear.