How a Rare APOE Variant Protects Against Alzheimer’s Disease

The goal of this project is to understand how APOE3-Christchurch confers its protective effect against Alzheimer’s disease onset, to inform therapy. Aim 1 is to examine the effects of apoE3-Ch on AD-related pathology and toxicity in amyloid model mice. We will look at the effects of astrocytic, hepatic, and systemic apoE3-Ch in early and late amyloid stages. Aim 2 is to define the functional consequences associated with altered biochemical properties of apoE3-Ch/lipoprotein particles. The biochemical and biophysical properties of non-lipidated and native, glia-secreted apoE3-Ch will be characterized. Then, their effects on neuronal homeostasis and AD-related pathologies will be assessed in iPSC-derived neurons and organoids.

Despite being the primary cause of dementia in the elderly, Alzheimer’s disease (AD) still has no cure. A great deal of effort is being deployed by scientists to better understand what goes wrong in the AD brain, which results in its deterioration. Apolipoprotein E (apoE) is a protein which principal function is to carry lipids and cholesterol throughout the body. There are various versions of apoE, the more common ones being apoE2, apoE3 and apoE4, each of them carrying a different level of risk to developing AD. In particular, apoE4 increases risk, while apoE3 is neutral and apoE2 is protective. Recently, a rare version of apoE called apoE3-Christchurch (apoE3-Ch) has been shown to be highly protective against AD. Using animal models of AD, we aim to investigate how apoE3-Ch protects the brain from the toxic effects of beta-amyloid accumulation in the brain. In parallel, we will also use stem cells to better understand the protective function of apoE3-Ch in human cells and cerebral organoids also known as “mini-brain”. We will evaluate what makes the apoE3-Ch protein different from the other, more common apoE proteins by looking at how their differences in amino acids, the building blocks that make up proteins, affect apoE3-Ch function in the brain. By understanding why this rare apoE protein is protective, our proposed research will shed light on the potential mechanisms underlying AD progression and suggest new therapeutic strategy to treat this devastating disease.

The greatest innovation pertains to the scope of this study. In addition to revealing any possible impact of apoE3-Ch on amyloid pathology for the first time, we aim to offer an extremely thorough characterization of, and comparison between, the biochemical function of apoE isoforms/lipoprotein particles. The identification of any differences between apoE3-Ch and apoE3 will deepen our understanding of which functional aspect of apoE is protective and which is detrimental; while any differences between apoE3-Ch and apoE2 may point to different possible protective pathways against Alzheimer’s.

With APOE being the main genetic modulator of sporadic Alzheimer’s disease onset, there is a great interest in the field in furthering our understanding of how apoE impacts disease progression. Grasping the full extent at which a genetic factor, such as APOE3-Ch, may be protective is as equally important as understanding how a factor may present a risk, as new therapeutic strategies could arise. The rise of apoE-targeted therapies would provide new avenues on how to prevent and/or treat Alzheimer’s disease.