Targeting Apolipoprotein E for Alzheimer’s Disease: An Industry Perspective

Abstract

Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and delivery of cholesterol in the brain. Humans have three common apoE isoforms, apoE2, apoE3 and apoE4, that show a strong genotype effect on the risk and age of onset for sporadic and late onset forms of Alzheimer’s disease (AD). Carriers of an ε4 allele have an increased risk of developing AD, while those with an ε2 allele are protected. Investigations into the contribution of apoE to the development of AD has yielded conflicting results and there is still much speculation about the role of this protein in disease. Here, we review the opposing hypotheses currently described in the literature and the approaches that have been considered for targeting apoE as a novel therapeutic strategy for AD. Additionally, we provide our perspective on the rationale for targeting apoE and the challenges that arise with respect to “drug-ability” of this target.

APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics

“…All the recent phase three clinical trials for AD failed, highlighting that this challenge always remains a priority. It is likely that AD has a spectrum of diseases without a common trigger, with slightly different initiators, accelerators and exacerbators ( Suidan and Ramaswamy, 2019 ). The mystery and ambiguity around the cause of AD is primarily what to blame for the lack of successful current therapeutics.…”

“…It has proven difficult to develop molecules that modify the conformation of APOE4 to APOE3 or APOE2 because the variable degree of lipidation of APOE may affect its tertiary conformation. On the other hand, for APOE4 homozygote patients, approaches aiming at apoE4 reduction may be sufficient ( Suidan and Ramaswamy, 2019 ). It is possible that such therapies slow the rate of cognitive decline in APOE4 carriers, but it is likely that the neurodegenerative process will not be completely halted ( Safieh et al, 2019 ).…”

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

“…Aerobic training also improved cognitive function (learning and memory) [ 201 ]. ABCA1 and ApoE are currently the matter of intensive research for AD treatment [ 202 ].…”

Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

“…Primary approaches to alter the amyloid-initiated cascade include immunotherapy, β-secretase 1 (BACE1) inhibitors, and vaccines. Potential mediators of Aβ toxicity, including the apolipoprotein E protein and microglial and glial activation [10][11][12], have also been targeted in preclinical and early-phase attempts. Strong evidence points toward a critical role for neurofibrillary tangles in the development of cognitive impairment, spurring on the development and testing of anti-tau therapies, with several clinical trials ongoing [8,13].…”