Alzheimer’s disease, the most common form of dementia, has had no potential treatments for decades. Previous research suggests that it is a complex, multifactorial disease where a patchwork of biological and lifestyle factors combine to increase or decrease risk.
However, a new study published in January in the journal Nature suggests that the risk of developing the disease is primarily determined by one important gene called apolipoprotein E (APOE). People with the protective APOE gene are very unlikely to develop Alzheimer’s disease, although lifestyle and environmental factors can slightly raise or lower the risk for people with the susceptible genetic variant. And an astonishing 99% of the population carries at least one disease-causing version of the gene.
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Nolan Townsend, CEO of gene therapy company Lexio Therapeutics, which is developing treatments targeting this gene, said there are more than 900,000 people in the U.S. with the highest-risk type of APOE.
“No gene therapy has ever attempted to address a population of this size,” Townsend told LiveScience.
An elusive cure
For decades, there was no good treatment for Alzheimer’s disease. Until the advent of anti-amyloid antibodies like donanemab, which eliminates the characteristic amyloid plaques that characterize the disease, there were no drugs that could actually slow the progression of the disease. But these drugs, touted as the first disease-modifying treatments for the condition, have serious side effects, including brain swelling and microbleeds. Patients at highest risk for Alzheimer’s disease are also the most vulnerable to these side effects.
At first glance, the APOE gene does not seem to have much association with Alzheimer’s disease. The main role of the protein it encodes is to transport fat molecules through the bloodstream. However, the APOE protein also interacts closely with amyloid beta, a protein thought to be the best-known molecular cause of Alzheimer’s disease, which aggregates to form plaques, disrupting connections between neurons and causing inflammation.
There are three versions of the APOE gene: APOE2, APOE3, and APOE4, each of which encodes a slightly different version of the protein. For decades, researchers thought that APOE2 was a protective variant and APOE4 increased the risk of the disease. APOE3 was thought to neither increase nor decrease risk.
However, APOE2 was underestimated in past studies. This allele is present in less than 1% of the population. A new Nature study examining data from 450,000 people reveals the true contribution of this trio of genes. Research has shown that APOE3 is not neutral. In fact, it increases the risk of Alzheimer’s disease, albeit to a much lesser extent than APOE4. On the other hand, having two copies of APOE2 largely prevented people from developing Alzheimer’s disease.
It’s not clear why, but other studies in laboratory dishes have shown that the highest-risk variants of APOE inhibit supporting cells called glia from handling fat, which can lead to dysfunction and neuroinflammation. APOE4 also appears to increase cell death and impair a cell’s response to oxidative stress, an imbalance between antioxidants and reactive chemicals called free radicals. Synaptic plasticity, the ability to adaptively strengthen or weaken connections between brain cells, is also impaired.
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The study authors concluded that APOE3 and APOE4 together account for 72% to 93% of Alzheimer’s disease.
“Unless there is a strong potential risk from APOE ε3.” [APOE3] and ε4 [APOE4]almost all AD [Alzheimer’s disease] And half of all dementia cases will never develop,” the study authors wrote in their paper.
This finding is supported by other studies suggesting that APOE2 is strongly protective. A 2020 study found that people with two copies of APOE2 had a 200 times lower risk of developing Alzheimer’s disease than people with two copies of APOE4. Having just one copy of the APOE2 gene reduces your risk by 80 times.
This study raises the possibility that people with high-risk mutations can avoid the disease if they have one or two copies of the APOE2 version of the gene.
Gene therapy for the masses
That’s where gene therapy comes in.
Gene therapy has changed the lives of people with rare genetic diseases, such as the muscle-wasting disease spinal muscular atrophy (SMA) and a progressive blindness called retinal dystrophy. In these cases, treatment involves introducing a copy of the healthy gene into the tissue that lacks it.
However, these treatments target a small population. For example, SMA affects approximately 1 in 15,000 births in the United States. Some gene therapy approaches are customized for a single patient.
In contrast, the study estimates that about 28% of the population carries at least one copy of the highest-risk version of the APOE gene, which could benefit from this drug.
Mayur Parmar, a pharmacologist at NOVA Southeastern University in Florida, conducted research on APOE2 gene therapy in mice.
“As we have learned in recent years, APOE4 plays an important role in amyloid beta, tau, neuroinflammation, and oxidative stress. APOE4 could be a potential target, and APOE2 therapy could be effective by suppressing these effects,” Palmer told Live Science.
Now these ideas are being tested. New York City-based Lexeo Therapeutics is planning three safety and dosage clinical trials to increase protective APOE gene variants and reduce deleterious APOE gene variants in early Alzheimer’s disease patients with the highest-risk APOE4/APOE4 gene combination.
The first phase of their research is a combined safety and dose study that incorporates protective APOE2 gene variants into the brains of patients with early Alzheimer’s disease. The second study, which has not yet reached human testing, will instead include a version of APOE2 with the extremely rare Christchurch mutation, which is found in the brains of people who have severe amyloid plaque buildup but do not show symptoms of Alzheimer’s disease.
Researchers believe the Christchurch variant is like an enhanced version of APOE2, offering stronger neuroprotection. Finally, the team plans to test the addition of APOE2 in combination with the use of small pieces of RNA to suppress APOE4 gene expression, which they hope will increase the efficacy of the treatment.
The company’s initial safety studies showed that the therapy was well tolerated and reduced tau levels in most of the 15 participants recruited. Only the primary results of the study have been published, but Townsend said long-term cognitive data from the trial will eventually be made public.
The ability of APOE gene therapy to target multiple disease pathways has the potential to provide significant benefit to patients, but it is difficult to prove. Pharmaceutical companies like Lexeo need to select clinical outcomes, such as better memory retention and reduced amyloid accumulation, to prove to regulators that their treatments are effective. The clearest signs that a treatment is working are detected by behavioral and cognitive tests, Townsend said, but the trials tied to those results are vast in scope and cost. That’s because promising treatments can take years to take effect, and such tests themselves are quite expensive.
No gene therapy has ever attempted to address a population of this size.
Nolan Townsend, CEO of Lexeo Therapeutics
Pharmaceutical companies that developed anti-amyloid antibodies avoided this need because the U.S. Food and Drug Administration (FDA) agreed to consider reducing amyloid burden in the brain as a surrogate for improved cognition. However, this approach is controversial due to uncertain links between these molecular changes and cognitive benefits, and Townsend said the regulatory environment for gene therapy is less permissive.
“There is uncertainty in the regulatory framework and landscape for accelerating the approval of gene-focused approaches in this area,” Townsend said.
overcome the barrier
Another challenge is getting the gene into the brain cells that need it. Adeno-associated virus (AAV) is the vector of choice for gene therapy. Viruses such as AAV9 can bypass the blood-brain barrier and gain access to the brain. But scientists are still studying how to deliver AAV gene therapy to maximize blood-brain barrier penetration.
Gene therapy can also be injected directly into the brain, but this approach is not perfect either. Previous gene therapies that used this approach to deliver neuroprotective nerve growth factor (NGF) to patients with mild to moderate Alzheimer’s disease passed safety tests but did not improve symptoms. Palmer said follow-up studies showed that NGF therapy was not reaching the brain cells it needed most: cholinergic neurons in the basal forebrain. Vectors do not travel well through brain tissue, and the trial did not use tools to help clinicians assess whether they injected the right areas of the brain.
Instead, Lexeo introduced the gene therapy into the patient’s cerebrospinal fluid, which circulates through the spinal cord. This technology circumvents the blood-brain barrier and improves delivery throughout the brain. Townsend said the injection is a 40-minute outpatient procedure that accomplishes the goal of “bathing the brain with the vector.”
New research showing the negative effects of APOE3 opens the door to expanding the target population for these gene therapies, Townsend said.
“If we approach suppressing E4, [APOE4] If it works, there’s no reason why there shouldn’t be a parallel approach to suppressing E3. [APOE3]” Townsend said.
There is no silver bullet
Ultimately, gene therapy targeting APOE variants has the potential to benefit a vast number of people, which excites the field.
But treatment alone is likely not enough, said Dr. Shanshan Wang, an anesthesiologist at the University of California, San Diego. Wang is working on another gene therapy that he thinks could help protect damaged neurons. Even though APOE plays a big role in Alzheimer’s disease risk, it’s not the whole story.
“When you think about treating cancer or other diseases, do you use only one treatment?” Wang said. Cancer treatments have evolved by targeting multiple aspects of the disease simultaneously. “It’s always a combination.”
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