Despite the identification of the APOE gene as the strongest genetic link to late-onset Alzheimer's disease (AD) since 1993 and the subsequent advances in the understanding of AD pathogenesis, the development of effective consensus-directed treatment therapies has yet to be realized.

The hallmark diagnostic feature of AD is the accumulation of insoluble protein aggregates of both beta-amyloid and tau peptides, which include ApoE. These aggregations cause loss of synapse function early in pathogenesis and ultimately neurodegeneration.

In the September 29th issue of Science Translational Medicine, investigators at the Mayo Clinic, Jacksonville, Florida report on their observations that the rare APOE3-Jacksonville (APOE3-jac) variant is protective in reducing the risk for developing AD.

Principal investigator, Guojun Bu, Professor and Chair of the Department of Neuroscience, Mayo Clinic, Jacksonville told BioWorld Science, "We demonstrated that ApoE variants can affect Alzheimer's disease risk by changing the biochemical properties, which in this case is the aggregation. The lesson learned from the study is that ApoE aggregation can contribute to Alzheimer's pathology pathway and this has led us to consider designing therapeutic strategies to that can reduce ApoE aggregation and by extension, hopefully reduce the risk of Alzheimer's disease."

The bulk of the studies in the ApoE field have focused on why there is an increased risk associated with APOE4 gene allele, but Bu pointed out that there are also many other variants affecting AD risk besides the common forms -- APOE2, APOE3 and/or APOE4. Moreover, APOE4 does not only influence the likelihood of forming amyloid fibrils. Rather, it also causes many other things, including tau tangles, decreased metabolism and neurodegeneration, all of which may help explain why it increases AD risk.

What's in a name

The investigators previously reported that the APOE3-jac variant is genetically linked to AD risk in a 2014 study published in Molecular Neurodegeneration, but only recently decided to name it based on the city in which they work, similar to the APOE3-Christchurch (R136S) variant published in 2019 in Nature Medicine. The "Jacksonville" and "Christchurch" names make it easier to remember and discuss research, rather than using "V236E" and "R136S", respectively. Both variants are protective in reducing the risk for AD, with Christchurch likely reducing tau tangles, while not reducing beta amyloidopathies as significantly.

APO3-jac is a rare variant, occurring with a prevalence typically less than 1%, but the investigators succeeded in finding three postmortem brains from human cases which enabled them to determine that APOE3-jac was protective, to assess brain amyloid deposition, ApoE aggregation status, and then extend studies performing biochemical assays and animal studies that confirmed the underlying mechanism for the Jacksonville variant reducing AD risk was by reducing ApoE aggregation.

Biochemical analysis revealed that the ApoE naturally forms oligomers, and the APOE3-jac variant was less likely to aggregate. Their experiments revealed that ApoE must be in the monomeric form to bind, transport, and deliver lipids via the ApoE receptor to cells. This process is critical to the formation and strengthening of synapses.

For animal studies, the investigators used adeno-associated virus (AAV) expressing APOE3-jac to make the variant and then they performed unbiased lipidomic analysis to determine how this affected the delivery of various lipids that are known to be required for myelination and synaptogenesis since loss of synapses is an early event in the development of Alzheimer's disease. They observed increases in several classes of lipids known to be critical for synaptic functions including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatides.

Importantly, the APOE3-V236E substitution is the first AD-associated variant within the region critical for APOE oligomerization and the requisite binding of lipids to serve ApoE function.

Bu explained that the function of ApoE involves the transport and delivery of lipids to the correct cells possessing the ApoE receptor. He emphasized that cholesterol is particularly important in the brain, where it accounts for about 25% of the body's total cholesterol. Typically, any cholesterol can diffuse, but with ApoE carrying these lipids it is much more efficiently delivered to where the lipids are needed to promote synapse formation and strengthening the synapses.

The work demonstrates that any variant that reduces the tendency to form ApoE aggregates is more likely to be lipidated, to be a better lipid transporter, and by extension is likely to increase the ability to support synapses.

However, Bu qualified the current state of ApoE aggregation research by stating that researchers do not currently know to what extent ApoE aggregates except in the beta amyloid plaque. There is ApoE aggregation in the intracellular compartment (endosomes), but whether ApoE exists primarily as an aggregate or a monomer is not known.

Looking forward, the investigators are enthusiastically pursuing translational potential with intent to identify therapeutic strategies that reduce ApoE aggregation and hopefully reduce the risk and/or progression of Alzheimer's disease.