Abstract
Alzheimer’s disease (AD) is the leading cause of dementia affecting almost 50 million people worldwide. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous APOE4 carriers being approximately 15-times more likely to develop the disease. With 25% of the population being APOE4 carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial. Though the exact mechanism by which ε4 allele increases the risk for AD is unknown, the processes mediated by APOE, including cholesterol transport, synapse formation, modulation of neurite outgrowth, synaptic plasticity, destabilization of microtubules, and β-amyloid clearance, suggest potential therapeutic targets. This review will summarize the impact of APOE on neurons and neuronal signaling, the interactions between APOE and AD pathology, and the association with memory decline. We will then describe current treatments targeting APOE4, complications associated with the current therapies, and suggestions for future areas of research and treatment.
Highlights
As the sixth leading cause of death, killing more than breast and prostate cancers combined, Alzheimer’s disease (AD) cannot be prevented, slowed, or cured [1]
Future studies should be conducted to evaluate the ability of rapamycin to prevent or slow AD disease progression long term, with treatment beginning in very early stages perhaps in a humanized apolipoprotein E (APOE) model exhibiting amyloid and τ pathology
Since APOE4-mediated insulin resistance can contribute to impaired cognition and dementia, targeting the glucose metabolic pathways to reduce the glycemic load in brain could be an alternative therapeutic approach to mitigate the APOE4-mediated effects
Summary
The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous APOE4 carriers being approximately 15-times more likely to develop the disease. With 25% of the population being APOE4 carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial. Though the exact mechanism by which ε4 allele increases the risk for AD is unknown, the processes mediated by APOE, including cholesterol transport, synapse formation, modulation of neurite outgrowth, synaptic plasticity, destabilization of microtubules, and β-amyloid clearance, suggest potential therapeutic targets. We will describe current treatments targeting APOE4, complications associated with the current therapies, and suggestions for future areas of research and treatment. Accepted Manuscript Online: 08 April 2019 Version of Record published: 18 April 2019
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