Alzheimer’s APOE4 genetic risk focused on promising trial
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 patients’ brains.
The trial included only five patients with a particular genetic risk for Alzheimer’s disease. They received a very low dose of gene therapy — a safety test, which the treatment passed. But the preliminary results, published on Friday during Alzheimer’s Disease Clinical Trials 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, dropped. These findings were promising enough to move the clinical trial to the next phase.
Five more patients are being treated at the higher dose, and the work, which was 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 chairman of genetic medicine at Weill Cornell Medicine in New York. We hope to get a stronger response, which will eventually lead to treatments that could slow the disease in those who have started it or, better yet, protect people at high risk who have no symptoms.
Experts not involved in the trial are fascinated.
“It’s a very provocative, very intriguing approach,” said Dr. Eliezer Masliah, director of the division of neuroscience at the National Institute on Aging.
Participants in study are among the roughly 2 percent of people who have inherited a pair of copies of the gene, APOE4, which significantly increases their risk of Alzheimer’s disease. For the subjects in the study, the first symptoms of Alzheimer’s disease had already appeared — their genetic risk had played out and they had few options. There is no treatment that specifically targets APOE4-driven Alzheimer’s disease, nor is it on the horizon.
“We’ve known about this risk factor for almost 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 reverse the effects of APOE4 or treat it with drugs, but to no avail.
With readily available genetic tests like 23andMe, more and more people are finding out they have two copies of APOE4. For some, e.g Chris Hemsworth, 39-year-old “Thor” star, knowledge changes life. By an incredible coincidence, he received a genetic test as part of a documentary show he was filming about life extension. When he found out the result, he made up his mind take a break from actinMr.
It is not clear exactly how APOE4 increases the likelihood of Alzheimer’s disease or why some people with two copies of the variant never develop the disease.
What is known is that APOE4 is one of three gene variants that affect a person’s chance of developing Alzheimer’s disease. The others are APOE3 and APOE2. Each person inherits two variants of the APOE gene, and the combination determines the risk.
Compared to the most common variant, APOE3, having at least one copy of the APOE4 variant increases the risk, and having the APOE2 variant reduces the risk.
But estimating lifetime risk from these variants is tricky. The best data, said Dr. Deborah L. Blacker, a geriatric psychiatrist and epidemiologist at Massachusetts General Hospital, shows that life risk Alzheimer’s disease for those with two APOE4 genes is 30 to 55 percent. The lifetime risk in people with one APOE4 gene and one APOE2 gene has not been directly assessed, but appears to be about 20 percent, Dr. Blacker said.
This leads to the idea that if gene therapy floods the brain with APOE2, turning the brain milieu of a person with two APOE4 variants into one that resembles that of a person with one APOE4 and one APOE2, it could possibly cut the risk of Alzheimer’s in half.
Recruitment to try the technique has been slow, said Dr. Sam Gandy, a professor of Alzheimer’s disease research at Mount Sinai in New York, who was one of the study’s investigators. Not everyone wants to sign up to have a gene-carrying virus injected into their brain.
But, he said, Alzheimer’s disease is so dire and people with two copies of APOE4 are in such danger that “desperate times call for desperate measures.”
The idea of APOE2 gene therapy emerged 25 years ago, when both gene therapy and the discovery of APOE variants were in their infancy. Three researchers who were then at Rockefeller University—Dr. Michael G. Kaplitt, now professor of neurological surgery at Weill Cornell Medicine, Dr. Gandy and Dr. Paul Greengard — published an essay suggesting that.
But, Dr. Kaplitt said, the technologies at the time were not enough and researchers were busy with other projects.
The idea, he said, “faltered”.
Now, with advances making this feasible, researchers can use a harmless virus, AAV, to deliver copies of the APOE2 gene into the brain. The virus and its genetic cargo reach the brain after direct injection into the spinal fluid.
dr. Kaplitt, who is leading the trial, said he was not involved with Lexeo for ethical reasons.
dr. Robert C. Green, a medical geneticist at Harvard who has studied how people react to learning their APOE4 status, cautioned against jumping to conclusions based on so little data from such a small study. However, he is not ready to dismiss it immediately.
“It could be an idea for a Hail Mary treatment for Alzheimer’s disease,” he said. But “as a proof of concept,” he said, “I’m impressed.”