Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Abstract

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.

CAIDE Dementia Risk Score and biomarkers of neurodegeneration in memory clinic patients without dementia

“…Cardiovascular risk factors, confluent white matter lesions, MTA and central atrophy have been shown to increase the AD-likelihood of SCI subjects (Garcia-Ptacek et al, 2014). The association of lower Aβ1-42 with higher CAIDE Dementia Risk Score including APOE (but not the risk score version without APOE) could be explained by the well-known contribution of the APOE ε4 allele to Aβ deposition and neurodegeneration (Liu et al, 2013). APOE ε4 seems to be related to increased Aβ deposition independently of cognitive performance (e.g.…”

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

“…The apolipoprotein E4 (APOEε4) allele is present in about 25–30% of the general population and 40% of AD, which also runs in the family. Individuals carrying the ε4 allele are at increased risk of AD compared to those carrying the more common ε3 allele [11]. APOEε4 is a major cholesterol carrier that supports lipid transport and injury repair in the brain.…”

Lipoproteins and Diseases of the Brain

“…In contrast, apoE2 and E3 bind to various sizes of lipids in more ways that are efficient and thus facilitate lipid transport between cells in the brain. The lipidated apoE can be internalized into cells in the brain (i.e., astrocytes, microglia, and neurons) through the family of low-density lipoprotein receptors (LDLR), low-density lipoprotein receptor-related protein 1 (LRP1), or heparan sulfate proteoglycans (HSPGs) [11,16].…”

“…It still remains unclear however, if apoE and ospA interact directly with neurons to disrupt the structure and function of the brain, whereas it is documented extensively that these lipoproteins induce pathological states via amyloid beta (Aβ) aggregation [15,16] and immune activation of microglia and astrocytes [17,18]. To address the absence of direct evidence of interaction between lipoproteins and neurons, we have studied the effect of apoE4 and ospA on neurons in terms of axonal outgrowth and synaptic loss.…”