Alzheimer’s disease, the most common form of dementia, has rebuffed potential treatments for decades. Previous research suggested that it was a complicated, multifactorial disease in which a patchwork of biological and lifestyle factors combined to increase or decrease risk.
But a new study published in January in the journal Nature suggests that the risk of developing the disease is largely determined by one key gene, called apolipoprotein E (APOE). Lifestyle and environmental factors can reduce the risk modestly up or down in people with susceptible gene variants, but those who have protective versions of the APOE gene are extremely unlikely to develop Alzheimer’s. And a staggering 99% of the population carries at least one disease-causing version of the gene.
The article continues below
There are more than 900,000 people in the United States who have the highest-risk form of APOE, he said Nolan Townsend, CEO of the gene therapy company Lexeo Therapeutics, which is developing a therapy aimed at the gene.
“There has been no gene therapy to date that has attempted to address a population of that size,” Townsend told LiveScience.
An elusive treatment
For decades, there were no good treatments for Alzheimer’s disease. No medication actually slowed the progression of the disease before the arrival of anti-amyloid antibodies such as donanemab, which removes the characteristic amyloid plaques that are a hallmark of the disease. But these drugs, touted as the first disease-modifying treatments for the condition, have serious side effectsincluding swelling and microhemorrhages in the brain. The patients who are most susceptible to Alzheimer’s are also most vulnerable to these side effects.
At first glance, APOE the gene does not seem particularly relevant to Alzheimer’s disease. The main role of the protein it codes for is to transport fat molecules through the blood. However, the APOE protein also closely interacts with what is considered the best-known molecular culprit in Alzheimer’s: the protein amyloid-beta, which accumulates into plaques that destroy connections between neurons and trigger inflammation.
There are three versions of the APOE gene – APOE2, APOE3 and APOE4 – and each codes for a slightly different version of the protein. For decades, scientists believed that APOE2 was a protective variant, while APOE4 increased the risk of the disease. APOE3 was thought to neither increase nor decrease risk.
However, in previous work, APOE2 was underrepresented; the allele is present in less than 1% of the population. In the new Nature study, which looked at data from 450,000 people, the true contribution of the genius trio was revealed. APOE3 is not neutral, the study found; rather, it increases Alzheimer’s risk, albeit to a much lesser degree than APOE4 does. Carrying two copies of APOE2, meanwhile, made people almost immune to developing Alzheimer’s.
It is not clear why, but other research in laboratory dishes shows that the highest risk variant of APOE impairs the processing of fat in support cells called glia and that this can trigger dysfunction and neuroinflammation. APOE4 also appears to do so increase cell death and impair how well cells respond to oxidative stressa state of imbalance between antioxidants and reactive chemicals called free radicals. It also impairs synaptic plasticity, or the ability to adaptively strengthen or weaken connections between brain cells.
The study authors concluded that APOE3 and APOE4 together are responsible for between 72% and 93% of Alzheimer’s disease cases.
“Without strong underlying risks from APOE ε3 (APOE3) and ε4 (APOE4), almost all AD (Alzheimer’s disease) and half of all dementia would not occur,” the study authors noted in the paper.
This finding is supported by other work suggesting that APOE2 is strongly protective. ONE 2020 study found that someone with two copies of APOE2 has one 200 times lower risk of developing Alzheimer’s than someone with two copies of APOE4. Carrying just one copy of the APOE2 gene reduces the risk 80-fold.
The research raises the possibility that people with higher-risk variants could stave off the disease if they had one or two copies of the APOE2 version of the gene.
Gene therapy for the masses
This is where gene therapy comes in.
Gene therapy has changed the lives of people with rare genetic disorders, such as muscle wasting disease spinal muscular atrophy (SMA) and a progressive form of blindness called retinal dystrophy. In these cases, the therapy involves delivering a copy of a healthy gene into a tissue that lacks it.
But these treatments target small populations; SMA affects, for example, approx 1 in 15,000 live births in the United States. Some gene therapy approaches are adapted to a single patient only.
In contrast, the study estimates that approximately 28% of the population has at least one copy of the highest-risk versions of the APOE gene that could potentially benefit from this drug.
Mayur Parmara pharmacologist at NOVA Southeastern University in Florida, has performed studies of APOE2 gene therapies in mice.
“As we’ve learned in recent years, APOE4 plays an important role in amyloid beta, tau, neuroinflammation and oxidative stress. It could be a potential target,” Parmar told LiveScience. APOE2 therapies could work by suppressing these effects, he added.
Now these ideas are being put to the test. New York City-based Lexeo Therapeutics plan tree safety and dosage clinically trials to increase protective APOE gene variants and decrease harmful APOE gene variants in people with the high-risk APOE4/APOE4 gene combination who have early Alzheimer’s disease.
The first phase of their research is a combined safety and dosage study that includes the protective APOE2 gene variant into the brains of people with early Alzheimer’s. Another study, which has not yet reached the human testing phase, will instead add a version of APOE2 that has the ultra-rare Christchurch mutation, a rare variant found in the brains of people who show no Alzheimer’s symptoms despite having built up severe amyloid plaques.
Scientists believe Christchurch variant is like a souped-up version of APOE2 that will offer even more neuroprotection. Finally, the team is planning a trial that combines the addition of APOE2 with the use of tiny pieces of RNA to suppress APOE4 gene expression, which they hope will enhance the therapeutic effect.
The company’s initial safety testing showed that the therapy was well tolerated and reduced tau levels in most of the 15 participants recruited. Only top-line results from the study have been published, although Townsend said long-term cognitive data from the study will eventually be released.
The ability of APOE gene therapies to target multiple disease pathways may offer significant benefits to patients, but will be difficult to prove. Pharmaceutical companies like Lexeo must choose a clinical outcome, such as better memory retention or less amyloid buildup, to demonstrate to regulators that their therapies work. The most obvious signs that a therapy is working are detected through behavioral and cognitive tests, but trials tied to those outcomes are enormous in scope and cost, Townsend said. That’s because it can take years for the effects of a promising treatment to manifest, and because such testing is quite expensive on its own.
There has been no gene therapy to date that has attempted to address a population of that size
Nolan Townsend, CEO of Lexeo Therapeutics
The pharmaceutical companies that developed anti-amyloid antibodies circumvented this need because the US Food and Drug Administration (FDA) agreed to see reduced brain amyloid load as a proxy for cognitive improvement. However, this approach has been controversial because of the uncertain link between these molecular changes and cognitive benefits, and Townsend said the regulatory environment for genetic therapies is less permissive.
“There is uncertainty in the regulatory frameworks and the landscape to get an accelerated approval of a genetic-focused approach in this area,” Townsend said.
Crossing the barrier
Another challenge is getting the gene into the brain cells that need it. Adeno-associated viruses (AAV) have been selected vector for gene therapy. Viruses such as AAV9 can bypass the blood-brain barrier and gain access to the brain. But researchers are still working on how to deliver AAV gene therapies to maximize the blood-brain barrier penetration.
Gene therapy can be injected directly into the brain, but this approach is also not perfect. An earlier one gene therapy 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. Parmar said follow-up work showed that the NGF therapy did not reach cholinergic neurons in the basal forebrain, the brain cells that needed it most. The vector failed to move well within brain tissue, and the experiment did not use tools that would have helped clinicians assess whether they had injected the right areas of the brain.
Lexeo has instead delivered its gene therapy into patients’ cerebrospinal fluid, which circulates through the spinal cord – a technique that bypasses the blood-brain barrier and improves brain-wide delivery. The injection is a 40-minute outpatient procedure, Townsend said, and will achieve their goal of “bathing the brain in the vector.”
The new study showing the negative effects of APOE3 opens the door to expanding the target population for these gene therapies, Townsend said.
“If the approach to suppress E4 (APOE4) works, then there’s no reason why there couldn’t be a parallel approach to suppress E3 (APOE3),” Townsend said.
No silver bullet
Ultimately, gene therapies targeting APOE variants have excited the field because they could potentially benefit large numbers of people.
But no single treatment is likely to be sufficient, he said Dr. Shanshan Wangan anesthesiologist at the University of California, San Diego. Wang is working on a separate gene therapy which she believes may help protect damaged neurons. That’s because, while APOE has a big role in Alzheimer’s risk, it’s not the whole story.
“When you think about cancer treatment or any other disease treatment, do you use only one therapy?” Wang said. Cancer treatment has thrived by targeting several facets of the disease at the same time. “It’s always combinatorial.”
