Abstract
Apolipoprotein E (APOE) has three different isoforms, with APOE4 carriers representing a major risk factor for the development of Alzheimer’s disease (AD). AD is the most common form of dementia, and is a relentlessly progressive disorder that afflicts the aged, characterized by severe memory loss. Presently, AD does not have a cure, increasing the urgency for the development of novel therapeutics for the prevention/treatment of AD. The APOE4 isoform is associated with many pathological mechanisms, such as increased neuroinflammation and a reduction in β-amyloid (Aβ) clearance. The accumulation of Aβ plaques in the brain is a hallmark of AD. The presence of APOE4 can increase neuroinflammation via overactivation of the nuclear factor kappa B (NF-κB) pathway. The NF-κB pathway is a family of transcription factors involved with regulating over 400 genes involved with inflammation. AD is associated with sustained inflammation and an overactivation of the NF-κB pathway. Therefore, targeting the APOE4 isoform and suppressing the NF-κB pathway using anti-inflammatory compounds may result in the development of novel therapeutics for the prevention/treatment of AD.
Highlights
The global population is reaching unprecedented levels of advanced age, generating a large demographic vulnerable to brain insults, creating enormous healthcare, economic and social impacts
Alzheimer’s disease (AD) is associated with sustained inflammation, which in part may be due to the Receptor for Advanced Glycation End-Products (RAGE)/NF-κB axis, which activates an autoregulatory loop that further amplifies neuroinflammation [33]
Targeting the APOE4 isoform may suppress the NF-κB pathway, given that the weak binding of APOE4 to LRP1 leads to increased NF-κB activity
Summary
The global population is reaching unprecedented levels of advanced age, generating a large demographic vulnerable to brain insults, creating enormous healthcare, economic and social impacts. The presence of Aβ plaques does not always result in AD, which has led to controversy over the use of aducanumab. APOE is a cholesterol carrier that is involved with lipid transportation and repair in the brain [6]. APOE is a polymorphic protein with three isoforms, APOE4, APOE3, and APOE2, which differ from each other by two amino acid substitutions (arg/arg, cys/arg, and cys/cys, respectively), resulting in different tertiary structures and likely altering APOE function. Despite the similarity among the isoforms, they present major differences in the risk of developing AD, with APOE4 being a strong risk factor for the development of AD. Genome-wide association studies have shown that APOE4 is the strongest genetic risk factor for early-onset AD and late-onset AD [8,9].
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call