Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder which causes progressive cognitive decline. The majority of AD cases are sporadic and late-onset (> 65 years old) making it the leading cause of dementia in the elderly. While both genetic and environmental factors contribute to the development of late-onset AD (LOAD), APOE polymorphism is a major genetic risk determinant for LOAD. In humans, the APOE gene has three major allelic variants: ε2, ε3 and ε4, of which APOE ε4 is the strongest genetic risk factor for LOAD, whereas APOE ε2 is protective. Mounting evidence suggests that APOE ε4 contributes to AD pathogenesis through multiple pathways including facilitated amyloid-β deposition, increased tangle formation, synaptic dysfunction, exacerbated neuroinflammation and cerebrovascular defects. Since APOE modulates multiple biological processes through its corresponding protein apolipoprotein E (apoE), APOE gene and apoE properties have been a promising target for therapy and drug development against AD. In this review, we summarize the current evidence regarding how the APOE ε4 allele contributes to the pathogenesis of AD and how relevant therapeutic approaches can be developed to target apoE-mediated pathways in AD.

Lipid-modifying efficacy and tolerability of anacetrapib added to ongoing statin therapy in Japanese patients with dyslipidemia

“…Consistent with previous studies, anacetrapib 100 mg also significantly increased Apo E, a component of HDL and VLDL particles [13]. ApoE protein plays many important roles in the body, including transporting cholesterol and cholesterol-like molecules, like beta-amyloid, in and out of cells [22]. Plasma levels of TG and VLDL-C also were significantly reduced relative to placebo at Week 24.…”

Alzheimer’s disease: experimental models and reality

“…This is particularly important to consider when testing therapeutics that target these interactions. The latter has been critical in the development and preclinical testing of therapeutic approaches that target the interaction between apoE and Aβ [110, 128, 176]. …”

HDL mimetic peptides affect apolipoprotein E metabolism: equal supplement or functional enhancer?

“…Therefore, it would be expected that supplementation of non‐risk ApoE proteins (i.e., ApoE2/3), which would compensate for the reduced neuroprotective function of ApoE either due to decreased levels or lipidation, is a promising target for drug development and therapy against AD (Yamazaki et al . ). Two common approaches were proposed: one approach is to transduce engineered adenoviral vectors to express human ApoE2 or ApoE3 proteins; another one is to supplement functional equivalents mimetic peptides of holo‐proteins.…”

“…While ApoE isoform‐specific lipoprotein preferences with ApoE4 being preferentially associated with LDL/very low density lipoprotein and ApoE2/3 with high‐density lipoproteins (HDL) were noted in the plasma, in the brain, ApoE is associated predominantly with cholesterol and phospholipid‐rich, HDL particles without any known isoform specificity (Yamazaki et al . ), suggesting a pathogenic mechanism that is not directly linked to isoform‐specific effects on lipid metabolism in the brain.…”