Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease

Apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer disease (AD); the 14 allele increases risk and the 12 allele is protective. In the central nervous system (CNS), apoE is produced by glial cells, is present in high-density-like lipoproteins, interacts with several receptors that are members of the low-density lipoprotein receptor (LDLR) family, and is a protein that binds to the amyloid-b (Ab) peptide. There are a variety of mechanisms by which apoE isoform may influence risk for AD. There is substantial evidence that differential effects of apoE isoform on AD risk are influenced by the ability of apoE to affect Ab aggregation and clearance in the brain. Other mechanisms are also likely to play a role in the ability of apoE to influence CNS function as well as AD, including effects on synaptic plasticity, cell signaling, lipid transport and metabolism, and neuroinflamma-tion. ApoE receptors, including LDLRs, Apoer2, very low-density lipoprotein receptors (VLDLRs), and lipoprotein receptor-related protein 1 (LRP1) appear to influence both the CNS effects of apoE as well as Ab metabolism and toxicity. Therapeutic strategies based on apoE and apoE receptors may include influencing apoE/Ab interactions, apoE structure, apoE lipidation, LDLR receptor family member function, and signaling. Understanding th