Doctors plan to test a gene therapy that could prevent Alzheimer’s disease

No one knows for certain what causes Alzheimer’s disease. But one fact about the condition has gained nearly irrefutable status. Depending on what versions of a gene called APOE you inherit, your risk of the brain disorder can be half the average—or more than 12 times as high.

Sometimes called “the forgetting gene,” APOE comes in three common versions, called 2, 3, and 4. Type 2 lowers a person’s risk, 3 is average, and 4 increases the chance dramatically. The risk is so great that doctors avoid testing people for APOE because a bad result can be upsetting, and there’s nothing to do about it. There’s no cure, and you can’t change your genes, either.

Well, today you can’t. But doctors in New York City say that beginning in May, they will start testing a novel gene therapy in which people with the unluckiest APOE genes will be given a huge dose to their brain of the low-risk version.

If that slows the brain-wasting illness in people who already have Alzheimer’s, it could eventually lead to a way to prevent the disease. The clinical trial, led by Ronald Crystal at Weill Cornell Medicine in Manhattan, is a novel tactic against dementia as well as a new twist for gene therapy. Most gene replacement efforts, which rely on viruses to carry DNA instructions into a person’s cells, aim to fix rare diseases such as hemophilia by replacing a single malfunctioning gene.

But common diseases don’t have singular causes, so gene therapy has never seemed as promising. The Alliance for Regenerative Medicine, a trade group, says it knows of no gene therapies currently being tried on patients with Alzheimer’s disease.

“It seems like a long shot to go into human clinical trials, but there’s a desperate need for any treatment,” says Kiran Musunuru, a professor at the University of Pennsylvania's medical school. Musunuru, who studies genetic treatments for heart disease, says the experiment planned in New York represents a new category of gene therapy in which the aim isn’t to cure, but to “reduce the risk of future disease in healthy people.”

Crystal says his plan also sidesteps the debate over the true cause of Alzheimer’s disease, which has become a multibillion-dollar roulette wheel where drug companies, and patients, keep losing. In January, Roche called off two big studies of an antibody meant to clear up characteristic plaques of a protein called beta-amyloid, the latest blow to the theory that these plaques around neurons are the fundamental cause of Alzheimer’s.

“There are those in the field that believe strongly that amyloid does it,” says Crystal, while others think it’s another protein called tau, tangles of which are found in dying neurons. “Probably the answer is that it’s very complex,” he says. “The approach we took is to ignore all that and think about it from a genetic point of view.”

In doing so, Crystal’s team is relying on a 25-year-old discovery. In the 1990s, researchers at Duke University went fishing for any proteins they could find attached to amyloid plaques. They identified apolipoprotein-e, the protein encoded by the APOE gene. By sequencing the gene in 121 patients, they determined that one version, APOE4, was inexplicably common in those suffering from the disease.

The gene's function still isn’t fully understood (it has a role in transporting cholesterol and fats) but its status as a risk factor remains fearsome. According to the Alzheimer’s Association,  about 65% of people with Alzheimer’s have at least one copy of the risky gene. For people born with two high-risk copies, one from each parent, dementia becomes close to a sure thing if they live long enough. 

However, some people inherit one 4 and one 2, the lowest-risk version of the gene. Those individuals have closer to the average risk, suggesting that the protective version of the gene is offsetting the risky one.

This is the effect the Weill Cornell doctors will try to copy. The center is now looking for people with two copies of the high-risk gene who already have memory loss, or even a diagnosis of Alzheimer’s. Starting in about a month, Crystal says, the first volunteers will receive an infusion into their spinal cords of billion of viruses carrying the 2 gene.

On the basis of tests in monkeys, Crystal expects the viruses to spread the lucky gene to cells throughout the patients’ brains. Mice treated in the same way, his center found, accumulated less amyloid in their brains.

The strategy, Crystal says, doesn’t depend on knowing everything about what really causes the illness. “What attracts us to Alzheimer’s is that the genetic epidemiology is so obvious,” he says. “So the strategy is, can we bathe the brain in E2? We have the infrastructure to do it, so we thought, why not? It gets around the problem of the mechanism of the disease.”

“The concept is rational,” Crystal adds. “Whether it works in a human is another thing.”

The New York study is preliminary. Crystal says his team needs to determine if the added gene is even functioning at a detectable level. Doctors will draw spinal fluid from the patients and see if it contains the expected mix of proteins—the expected type 4, but now with an equal or greater amount of 2 mixed in.

By the time people start forgetting names and where the car keys are, it’s a result of brain changes that began taking place a decade before. That means the patients who join the trial can’t expect much. It’s probably too late for them.

Even so, the Alzheimer’s Drug Discovery Foundation is giving Crystal $3 million to pay for the study, its largest grant to date. “We don’t know yet what will happen,” says Nick McKeehan, an assistant director at the foundation. “But it’s a stepping stone. Maybe we will need to treat people earlier. It’s opening the door for this type of therapy.”

Eventually, the hope is, middle-aged people with risky genes might undergo one-time genetic tune-ups. Even a small reduction in the pace at which brain changes occur could make a difference over time.

“Alzheimer’s is the most feared disease in the world, because losing your mind is horrifying. People would rather have cancer or a heart attack,” says Susan Hahn, a genetic counselor who doesn’t think people should get their APOE gene tested without good reasons. “You have to be prepared for what you are going to hear, because it’s permanent. You can’t change your genes—although maybe with this study you can.”