A Serendipitous Genetic Fluke Could Lead to a Revolutionary Treatment for Alzheimer's Disease

Researchers are zeroing in on genetic variants to find new treatments for neurodegenerative conditions.

Binary brain and genomic DNA on a dark blue particle background.
Yuichiro Chino/Moment/Getty Images

For devastating diseases like Alzheimer’s, nature rarely hands over a neat blueprint for engineering a potential cure. Sometimes, it's tucked away where you least expect it. Such was the case in 2019. In a family infamous for harrowing cases of early-onset Alzheimer’s disease, researchers discovered one member who was spared despite her brain showing signs of neurodegeneration.

The woman was found to carry two mutated copies of the gene APOE, known for its role in Alzheimer’s disease. Instead of putting her in malady’s crosshairs, the woman’s unique genetic variant called the Christchurch variant, protected her brain from collapsing into a deadly tangle of misfolded proteins.

Now, in a study published Wednesday in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, researchers channel this serendipitous genetic fluke into an antibody therapy dubbed 7C11, which prevented abnormal proteins called tau from clumping together in the brains and eyes of mice. (Clumping tau proteins are considered a hallmark of Alzheimer’s disease, leading to neurons dying and brain atrophy.)

The work is still early, Joseph F. Arboleda-Velasquez, a cell biologist at Massachusetts Eye and Ear in Boston who led the study, tells Inverse. But it's one he and his colleagues hope bears fruit with their antibody therapy, one day joining the ranks of immunotherapies like aducanumab (also known as Aduhelm), which received approval from the U.S. Food and Drug Administration in 2021 and lecanemab greenlit earlier this year.

Engineering an antibody

Antibody therapies like aducanumab and lecanemab work by sticking to amyloid — another group of proteins that misfold and accumulate as plaques in the brain, causing inflammation and cell death — and removing it. The antibody therapy developed by Arboleda-Velasquez’s team instead targets the interaction between the protein encoded by APOE, called apolipoprotein E (also known as ApoE), and other proteins called heparan sulfate proteoglycans.

Previous studies have found that heparan sulfate proteoglycans allow for amyloid plaques and tau tangles to happen in Alzheimer’s disease. However, with the Christchurch variant, this interaction is pretty much non-existent because the mutation makes ApoE unable to bind with heparan sulfate proteoglycans essentially. This, in turn, seems to snip amyloid plaques and tau tangles right in the bud.

To take advantage of this genetic cheat code, Arboleda-Velasquez says the researchers wanted to focus on designing an antibody that would silence the interaction between ApoE and the heparan sulfate proteoglycans, somewhat like a molecular muzzle. What makes antibodies great for that is that you can engineer them to recognize and target a particular protein sequence. In this case, that small difference in the protein sequence between the ApoE proteins associated with Alzheimer’s disease and the protective Christchurch ApoE.

After much tinkering, the researchers came up with an antibody called 7C11, which specifically binds to the part of the disease-causing ApoE proteins that would ordinarily interact with heparan sulfate proteoglycans. In mice genetically engineered to produce abnormal tau tangles, the researchers found their monoclonal antibody therapy sought out variants of ApoE that cause Alzheimer’s and considerably cut down the number of tau tangles in mousy brains and retinas.

Arboleda-Velasquez says they also tested the antibody on brain tissue collected from deceased individuals from that family with early-onset Alzheimer’s disease, which they obtained from a neurobank in Colombia.

“[Our collaborators] in Colombia shared with us some of that tissue to test whether or not the antibodies would bind to ApoE in the brain,” he says. “What we saw was very compelling. The antibodies bound to ApoE3 and 4 [other variants of the protein], and it did not bind to Christchurch that much, which we expected.”

A promising start news more research

While these initial results are encouraging, Arboleda-Velasquez says more extensive testing is needed before the antibody therapy can even be considered for human clinical trials.

“There are things I want to do with this research. Testing in other animal models will have value and testing for a longer period of time,” he says.

The researchers foresee the antibody 7C11 surpassing current antibody therapies like aducanumab and lecanemab since, at least right now, appears to be better at preventing abnormal tau tangles. There is also the possibility that this antibody therapy could one day be a prophylactic for people with a known risk for Alzheimer’s disease, says Arboleda-Velasquez.

All of this sounds incredibly promising, but it is important to remember how early in the process this research is. Further experiments, especially animal model testing, will provide a clearer picture of the impact this discovery could make.

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