In a new paper in Nature Medicine, an international team of neurologists makes the fascinating case that people with two copies of a gene called APOE4 aren’t just at risk for Alzheimer’s — they have a different form of the disease and are almost as likely to develop it. It is certain. By the age of 65, its story becomes a plaque in the brain. (Also read | How specific T cells in the brain slow the progression of Alzheimer’s disease: study,
The discovery comes with caveats, but still has near-term implications for the study, diagnosis, and treatment of the disease — especially given the advent of drugs like Lecambi, made by Eisai and Biogen, and donanemab, made by Eli Lilly & Co. Seeing it. It should also motivate the field to pursue treatments that specifically target the protein encoded by this gene.
It also raises a serious question for the public: Should more of us know if we are carriers of these genes?
Researchers have known for decades that people who have APOE4 have a higher risk of developing neurological conditions. One copy increases the chance of getting the disease up to three times, while two copies increase the risk 10 or more times. Many will remember movie star Chris Hemsworth’s 2022 revelation that he had two copies of the gene, news that reportedly inspired him to look at his life with a little more intention.
This new study puts a better point on that risk. Using two datasets involving more than 10,000 patients and more than 3,000 brain donors, the researchers show that people with two copies of the gene will almost inevitably develop biological symptoms of the disease. About 95% of people have deposits of a protein called amyloid in their brain and spinal fluid by age 65, a hallmark of Alzheimer’s disease. For this reason, the authors argue, it should be considered a distinct genetic form of the disease.
Those data make it tempting to consider these gene variants as the cause of disease. But it’s worth stopping for less than that – at least for now. A major hurdle is that although studies have shown that almost everyone in this group has amyloid plaques on their brains, we still cannot predict when, if at all, they will develop symptoms such as confusion and amnesia. Will also happen.
The other big caveat is that the people in the study all came from the US or Europe, and were predominantly white, leaving open the question of whether two copies of the gene cause the disease or whether other genetic and environmental factors play a role. Contribute to its evolution in the population, explains Jason Karlwisch, co-director of the Penn Memory Center at the University of Pennsylvania.
Still, Carlawish said via email, this is “a provocative study that presents a finding that, if verified, will change the way Alzheimer’s disease is classified, diagnosed, and treated.”
The most immediate impact may be to rethink when and how approved and experimental drugs are used. Author Risa Sperling, MD, director of the Alzheimer’s Research and Treatment Center at Brigham and Women’s Hospital, says this is solid evidence that Alzheimer’s can be detected in the brain many years before symptoms begin, “a way to try to intervene.” It’s an incredible opportunity.” Study. The benefits can be significant: About 2-3% of the population has two copies of APOE4, and this accounts for 15-20% of people with Alzheimer’s.
But it would be a bit difficult to interfere with existing drugs. Although the Food and Drug Administration last year approved Lecambi, a drug that clears amyloid plaques, it carries a warning that it could cause serious side effects in people with two copies of APOE4. And Lilly’s donanemab, which is currently under FDA review, poses a similar risk.
Patients with two copies of the gene are more likely to experience dangerous brain swelling or bleeding when taking the drugs. And in clinical studies, Lecambi didn’t do much to slow his cognitive decline, possibly because too much amyloid had accumulated in his brain by the time he was treated. Sperling thinks these new data suggest it is appropriate to use these drugs in this group of patients — but first, very carefully, and ideally in the context of clinical trials focused on prevention.
Future studies should differentiate people with one and two copies of APOE4, as their disease trajectories differ. Careful study of these patients over time may also yield broader lessons about how the disease manifests – and where and when to intervene. And more efforts should be put into tailoring treatments to people who carry these genes. A small pipeline of APOE4-targeted treatments has emerged, including gene therapy designed to increase production of APOE2, a form of the protein thought to be protective against the disease.
The public will undoubtedly wonder whether this means they should go out and get tested for the genes.
The question is one of deep debate. On the one hand, without treatment to interrupt the course of the disease, the consequences can only cause concern. On the other hand, people can make lifestyle changes, prepare for a future where they may need long-term care, or even seek clinical trials.
It would be wise to be more liberal in testing for people who come to the doctor’s office with vague symptoms, even if they are young. And of course, testing must be widespread if studies can pinpoint when and why biological signals will cause cognitive decline.
In the meantime, it is worth being optimistic: the development of medicine is moving forward and such studies may not only speed up the treatment of Alzheimer’s, but also reveal ways to prevent it.
