Promising study targets genetic risk of Alzheimer’s disease

In a bold attempt to halt the progression of some cases of Alzheimer’s disease, a group of researchers is trying something new: injecting a protective gene into the brains of patients.

The trial involved just five patients with a particular genetic risk for Alzheimer’s disease. They were given a very low dose of the gene therapy – a safety trial, in which the treatment passed. But preliminary results, announced Friday at the Clinical Trials for Alzheimer’s Disease conference, showed that proteins from the added gene appeared in the patients’ spinal fluid and brain levels of two markers of Alzheimer’s disease – tau and amyloid – fell. These findings were promising enough to move the clinical trial into its next phase.

Treatment of another five patients with a higher dose is ongoing, and the work, initially funded by the nonprofit Alzheimer’s Drug Discovery Foundation, is supported by Lexeo Therapeutics, a start-up company founded by Dr Ronald Crystal, who is also president of the department of genetic medicine at Weill Cornell Medicine in New York. The hope is to get a stronger response that leads to a treatment that can slow the disease in those who have already started or, better yet, protect high-risk people who don’t have symptoms.

Experts not involved in the test are fascinated.

“It’s a very provocative and intriguing approach,” said Dr. Eliezer Masliah, director of the division of neurosciences at the National Institute on Aging.

Study participants are among the roughly 2% of people who have inherited a pair of copies of the APOE4 gene, which significantly increases the risk of Alzheimer’s. For the study participants, the first symptoms of the disease had already appeared – their genetic risk had kicked in and they had few options. There is no specific treatment for Alzheimer’s disease caused by APOE4, nor are there any on the near horizon.

“We’ve known about this risk factor for nearly 30 years,” said Dr. Howard Fillit, co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation. His foundation and other funders have supported efforts to correct the effects of APOE4 or treat it with medication, but to no avail.

With genetic tests like 23andMe readily available, more and more people are finding that they have two copies of APOE4. For some, including Chris Hemsworth, the 39-year-old star of “Thor,” that information is life-changing. In an unlikely coincidence, he had the genetic test as part of a documentary he was making on life extension. Upon learning of the result, he decided to take a break from acting.

It’s not clear exactly how APOE4 makes Alzheimer’s more likely or why some people with two copies of the variant don’t have the disease.

What is known is that APOE4 is one of three genetic variants that affect a person’s chances of getting Alzheimer’s. The others are APOE3 and APOE2. Each person inherits two variants of the APOE gene, and the combination determines risk.

Compared to the most common variant, APOE3, having at least one copy of the APOE4 variant increases the risk, and having an APOE2 variant decreases the risk.

But estimating the lifetime risk conferred by these variants is tricky. The best data, said Dr. Deborah Blacker, a geriatric psychiatrist and epidemiologist at Massachusetts General Hospital, indicate that the lifetime risk of Alzheimer’s for those with two APOE4 genes is 30% to 55%. The lifetime risk in people with both an APOE4 gene and an APOE2 gene has not been estimated directly, but appears to be around 20%, Blacker said.

This leads to the idea that if gene therapy floods the brain with APOE2, converting the brain half of a person with two APOE4 variants into one that resembles that of a person with both APOE4 and APOE2, it could reduce the risk. of Alzheimer’s in half.

Recruitment to try the technique has been slow, said Dr. Sam Gandy, a research professor of Alzheimer’s disease at Mount Sinai in New York, who was one of the study’s investigators. Not everyone wants to sign up to have a virus carrying a gene injected into their brain.

But, he said, Alzheimer’s disease is so dire, and people with two copies of APOE4 are so at risk, that “desperate times call for desperate measures.”

The idea of ​​APOE2 gene therapy came about 25 years ago, when both gene therapy and the discovery of APOE variants were in their infancy. Three researchers who were at Rockefeller University – Dr Michael Kaplitt, now professor of neurological surgery at Weill Cornell Medicine, Gandy, and Dr Paul Greengard – published a paper suggesting this.

But the technologies at the time weren’t enough, and the researchers got busy with other projects, Kaplitt said.

The idea, he said, “languished”.

Today, with advances that make it possible, researchers are able to use a harmless virus, the AAV, to take copies of the APOE2 gene to the brain. The virus and its genetic payload reach the brain after being injected directly into the spinal fluid.

Kaplitt, who is leading the trial, said that for ethical reasons he is not involved with Lexeo.

Dr. Robert Green, a medical geneticist at Harvard who has studied how people respond to knowing their APOE4 status, cautioned against jumping to conclusions based on so little data from such a small study. However, he doesn’t want to discard it right away.

“It could be a miracle treatment idea for Alzheimer’s disease,” he said. But, “as a proof of concept, I’m impressed.”

Translated by Luiz Roberto M. Gonçalves