Apolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk for cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. ApoE–lipoproteins bind to several cell-surface receptors to deliver lipids and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. ApoE isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on ApoE in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different ApoE isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link ApoE4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting ApoE.

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of lateonset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk, relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The list of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration, and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism, and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

Background: TREM2 is associated with several neurodegenerative diseases. Results: ApoE bound to TREM2 and increased phagocytosis of apoptotic neurons by microglia. Alzheimer disease (AD) risk-associated TREM2-R47H mutant had a reduced binding to apoE. Conclusion: ApoE is a novel ligand for TREM2. Interaction between apoE and TREM2 likely regulates phagocytosis of apoEbound apoptotic neurons. Significance: Interaction between two AD risk-associated proteins modulates microglial function.