How Leqembi became the biggest news in Alzheimer’s disease in 40 years, and what comes next
A few months ago, Betsy Groves traveled less than a mile from her home in Cambridge, Mass. to give a talk to a bunch of scientists. The scientists, who worked for the pharmaceutical companies Biogen and Eisai, wanted to know how she lived her life, how she thought about her future, and what it was like when a doctor’s appointment in 2021 gave her the worst possible news. Groves, 73, has Alzheimer’s disease. She caught it early, through a lumbar puncture that showed evidence of amyloid, an Alzheimer’s hallmark, in her cerebrospinal fluid. As a way of dealing with her diagnosis, she joined the Alzheimer’s Association’s National Early-Stage Advisory Board, which helped her shift into seeing her diagnosis as something she could use to help others.
After her talk, Groves stayed for lunch with the scientists, who were eager to put a face to their work. Biogen and Eisai were about to release the first drug to successfully combat Alzheimer’s in 40 years of experimental disaster. Their drug, which is known by the scientific name lecanemab and the marketing name Leqembi, was granted accelerated approval by the U.S. Food and Drug Administration last Friday, Jan. 6, after a study in 1,800 people showed that it reduced cognitive decline by 27 percent over 18 months.
It is no exaggeration to say that this result is a huge deal. The field of Alzheimer’s drug development has been absolutely littered with failures. Almost everything researchers have tried has tanked in clinical trials. “Most of the things that we've done have proven not to be effective, and it's not because we haven’t been taking a ton of shots at goal,” says Anton Porsteinsson, director of the University of Rochester Alzheimer's Disease Care, Research, and Education Program, who worked on the lecanemab trial. “I think it's fair to say you don't survive in this field unless you're an eternal optimist.”
As far back as 1984, a cure looked like it was within reach: Scientists discovered that the sticky plaques that develop in the brains of those who have Alzheimer’s are made up of a protein fragment called beta-amyloid. Buildup of beta-amyloid seemed to be sufficient to disrupt communication between, and eventually kill, memory cells. If that was true, then the cure should be straightforward: Stop the buildup of beta-amyloid; stop the Alzheimer’s disease.
It wasn’t so simple. Over the next 38 years, hundreds of drugs designed either to interfere with the production of abnormal amyloid or to clear it from the brain flamed out in trials. It got so bad that neuroscience drug divisions at major pharmaceutical companies (AstraZeneca, Pfizer, Bristol-Myers, GSK, Amgen) closed one by one, leaving the field to smaller, scrappier companies, like Cambridge-based Biogen and Tokyo-based Eisai. Some scientists began to dismiss the amyloid hypothesis altogether: If this protein fragment was so important to the disease, why didn’t ridding the brain of it do anything for patients? There was another abnormal protein that showed up in the brains of Alzheimer’s patients, called tau. Some researchers defected to the tau camp, or came to believe the proteins caused damage in combination.
The situation came to a head in 2021, when the FDA granted provisional approval to a drug called aducanumab, marketed as Aduhelm, against the advice of its own advisory council. The approval was based on proof that Aduhelm reduced beta-amyloid in the brain, even though one research trial showed it had no effect on people’s symptoms or daily life. Aduhelm could also cause serious side effects, like brain swelling and amyloid related imaging abnormalities (known as ARIA, these are basically micro-bleeds that appear on MRI scans). Without a clear benefit to memory loss that would make these risks worth it, Medicare refused to pay for Aduhelm among the general population. Two congressional committees launched an investigation into the drug’s approval, citing corporate greed, lapses in protocol, and an unjustifiably high price. (Aduhelm was also produced by the pharmaceutical company Biogen.)
To be clear, Leqembi is not the cure Alzheimer’s researchers hope for. While the drug is the first to show clear signs of a clinical benefit, the scientific establishment is split on how much of a difference Leqembi will make in the real world.
So far, Leqembi is like Aduhelm in that it has been given accelerated approval only for its ability to remove amyloid from the brain. Both are monoclonal antibodies that direct the immune system to attack and clear dysfunctional beta-amyloid. The difference is that, while that’s all Aduhelm was ever shown to do, Leqembi’s makers have already asked the FDA to give it full approval – a decision that would increase the likelihood that Medicare will cover it – based on data that show it also improves Alzheimer’s sufferer’s lives. Leqembi targets a different type of amyloid, a soluble version called “protofibrils,” and that appears to change the effect. “It can give individuals and their families three, six months longer to be participating in daily life and living independently,” says Claire Sexton, PhD, senior director of scientific programs & outreach for the Alzheimer's Association. “These types of changes matter for individuals and for their families.”
To be clear, Leqembi is not the cure Alzheimer’s researchers hope for. It does not halt or reverse the disease, and people do not get better. While the drug is the first to show clear signs of a clinical benefit, the scientific establishment is split on how much of a difference Leqembi will make in the real world. It has “a rather small effect,” wrote NIH Alzheimer’s researcher Madhav Thambisetty, MD, PhD, in an email to Leaps.org. “It is unclear how meaningful this difference will be to patients, and it is unlikely that this level of difference will be obvious to a patient (or their caregivers).” Another issue is cost: Leqembi will become available to patients later this month, but Eisai is setting the price at $26,500 per year, meaning that very few patients will be able to afford it unless Medicare chooses to reimburse them for it.
The same side effects that plagued Aduhelm are common in Leqembi treatment as well. In many patients, amyloid doesn’t just accumulate around neurons, it also forms deposits in the walls of blood vessels. Blood vessels that are shot through with amyloid are more brittle. If you infuse a drug that targets amyloid, brittle blood vessels in the brain can develop leakage that results in swelling or bleeds. Most of these come with no symptoms, and are only seen during testing, which is why they are called “imaging abnormalities.” But in situations where patients have multiple diseases or are prescribed incompatible drugs, they can be serious enough to cause death. The three deaths reported from Leqembi treatment (so far) are enough to make Thambisetty wonder “how well the drug may be tolerated in real world clinical practice where patients are likely to be sicker and have multiple other medical conditions in contrast to carefully selected patients in clinical trials.”
Porsteinsson believes that earlier detection of Alzheimer’s disease will be the next great advance in treatment, a more important step forward than Leqembi’s approval.
Still, there are reasons to be excited. A successful Alzheimer’s drug can pave the way for combination studies, in which patients try a known effective drug alongside newer, more experimental ones; or preventative studies, which take place years before symptoms occur. It also represents enormous strides in researchers’ understanding of the disease. For example, drug dosages have increased massively—in some cases quadrupling—from the early days of Alzheimer’s research. And patient selection for studies has changed drastically as well. Doctors now know that you’ve got to catch the disease early, through PET-scans or CSF tests for amyloid, if you want any chance of changing its course.
Porsteinsson believes that earlier detection of Alzheimer’s disease will be the next great advance in treatment, a more important step forward than Leqembi’s approval. His lab already uses blood tests for different types of amyloid, for different types of tau, and for measures of neuroinflammation, neural damage, and synaptic health, but commercially available versions from companies like C2N, Quest, and Fuji Rebio are likely to hit the market in the next couple of years. “[They are] going to transform the diagnosis of Alzheimer's disease,” Porsteinsson says. “If someone is experiencing memory problems, their physicians will be able to order a blood test that will tell us if this is the result of changes in your brain due to Alzheimer's disease. It will ultimately make it much easier to identify people at a very early stage of the disease, where they are most likely to benefit from treatment.”
Learn more about new blood tests to detect Alzheimer's
Early detection can help patients for more philosophical reasons as well. Betsy Groves credits finding her Alzheimer’s early with giving her the space to understand and process the changes that were happening to her before they got so bad that she couldn’t. She has been able to update her legal documents and, through her role on the Advisory Group, help the Alzheimer’s Association with developing its programs and support services for people in the early stages of the disease. She still drives, and because she and her husband love to travel, they are hoping to get out of grey, rainy Cambridge and off to Texas or Arizona this spring.
Because her Alzheimer’s disease involves amyloid deposits (a “substantial portion” do not, says Claire Sexton, which is an additional complication for research), and has not yet reached an advanced stage, Groves may be a good candidate to try Leqembi. She says she’d welcome the opportunity to take it. If she can get access, Groves hopes the drug will give her more days to be fully functioning with her husband, daughters, and three grandchildren. Mostly, she avoids thinking about what the latter stages of Alzheimer’s might be like, but she knows the time will come when it will be her reality. “So whatever lecanemab can do to extend my more productive ways of engaging with relationships in the world,” she says. “I'll take that in a minute.”
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five:
- Kids stressing you out? They could be protecting your health.
- A new device unlocks the heart's secrets
- Super-ager gene transplants
- Surgeons could 3D print your organs before operations
- A skull cap looks into the brain like an fMRI
This article originally appeared in One Health/One Planet, a single-issue magazine that explores how climate change and other environmental shifts are making us more vulnerable to infectious diseases by land and by sea - and how scientists are working on solutions.
On a warm summer day, forests, meadows, and riverbanks should be abuzz with insects—from butterflies to beetles and bees. But bugs aren’t as abundant as they used to be, and that’s not a plus for people and the planet, scientists say. The declining numbers of insects, coupled with climate change, can have devastating effects for people in more ways than one. “Insects have been around for a very long time and can live well without humans, but humans cannot live without insects and the many services they provide to us,” says Philipp Lehmann, a researcher in the Department of Zoology at Stockholm University in Sweden. Their decline is not just bad, Lehmann adds. “It’s devastating news for humans.
”Insects and other invertebrates are the most diverse organisms on the planet. They fill most niches in terrestrial and aquatic environments and drive ecosystem functions. Many insects are also economically vital because they pollinate crops that humans depend on for food, including cereals, vegetables, fruits, and nuts. A paper published in PNAS notes that insects alone are worth more than $70 billion a year to the U.S. economy. In places where pollinators like honeybees are in decline, farmers now buy them from rearing facilities at steep prices rather than relying on “Mother Nature.”
And because many insects serve as food for other species—bats, birds and freshwater fish—they’re an integral part of the ecosystem’s food chain. “If you like to eat good food, you should thank an insect,” says Scott Hoffman Black, an ecologist and executive director of the Xerces Society for Invertebrate Conservation in Portland, Oregon. “And if you like birds in your trees and fish in your streams, you should be concerned with insect conservation.”
Deforestation, urbanization, and agricultural spread have eaten away at large swaths of insect habitat. The increasingly poorly controlled use of insecticides, which harms unintended species, and the proliferation of invasive insect species that disrupt native ecosystems compound the problem.
“There is not a single reason why insects are in decline,” says Jessica L. Ware, associate curator in the Division of Invertebrate Zoology at the American Museum of Natural History in New York, and president of the Entomological Society of America. “There are over one million described insect species, occupying different niches and responding to environmental stressors in different ways.”
Jessica Ware, an entomologist at the American Museum of Natural History, is using DNA methods to monitor insects.
In addition to habitat loss fueling the decline in insect populations, the other “major drivers” Ware identified are invasive species, climate change, pollution, and fluctuating levels of nitrogen, which play a major role in the lifecycle of plants, some of which serve as insect habitants and others as their food. “The causes of world insect population declines are, unfortunately, very easy to link to human activities,” Lehmann says.
Climate change will undoubtedly make the problem worse. “As temperatures start to rise, it can essentially make it too hot for some insects to survive,” says Emily McDermott, an assistant professor in the Department of Entomology and Plant Pathology at the University of Arkansas. “Conversely in other areas, it could potentially also allow other insects to expand their ranges.”
Without Pollinators Humans Will Starve
We may not think much of our planet’s getting warmer by only one degree Celsius, but it can spell catastrophe for many insects, plants, and animals, because it’s often accompanied by less rainfall. “Changes in precipitation patterns will have cascading consequences across the tree of life,” says David Wagner, a professor of ecology and evolutionary biology at the University of Connecticut. Insects, in particular, are “very vulnerable” because “they’re small and susceptible to drying.”
For instance, droughts have put the monarch butterfly at risk of being unable to find nectar to “recharge its engine” as it migrates from Canada and New England to Mexico for winter, where it enters a hibernation state until it journeys back in the spring. “The monarch is an iconic and a much-loved insect,” whose migration “is imperiled by climate change,” Wagner says.
Warming and drying trends in the Western United States are perhaps having an even more severe impact on insects than in the eastern region. As a result, “we are seeing fewer individual butterflies per year,” says Matt Forister, a professor of insect ecology at the University of Nevada, Reno.
There are hundreds of butterfly species in the United States and thousands in the world. They are pollinators and can serve as good indicators of other species’ health. “Although butterflies are only one group among many important pollinators, in general we assume that what’s bad for butterflies is probably bad for other insects,” says Forister, whose research focuses on butterflies. Climate change and habitat destruction are wreaking havoc on butterflies as well as plants, leading to a further indirect effect on caterpillars and butterflies.
Different insect species have different levels of sensitivity to environmental changes. For example, one-half of the bumblebee species in the United States are showing declines, whereas the other half are not, says Christina Grozinger, a professor of entomology at the Pennsylvania State University. Some species of bumble bees are even increasing in their range, seemingly resilient to environmental changes. But other pollinators are dwindling to the point that farmers have to buy from the rearing facilities, which is the case for the California almond industry. “This is a massive cost to the farmer, which could be provided for free, in case the local habitats supported these pollinators,” Lehmann says.
For bees and other insects, climate change can harm the plants they depend on for survival or have a negative impact on the insects directly. Overly rainy and hot conditions may limit flowering in plants or reduce the ability of a pollinator to forage and feed, which then decreases their reproductive success, resulting in dwindling populations, Grozinger explains.
“Nutritional deprivation can also make pollinators more sensitive to viruses and parasites and therefore cause disease spread,” she says. “There are many ways that climate change can reduce our pollinator populations and make it more difficult to grow the many fruit, vegetable and nut crops that depend on pollinators.”
Disease-Causing Insects Can Bring More Outbreaks
While some much-needed insects are declining, certain disease-causing species may be spreading and proliferating, which is another reason for human concern. Many mosquito types spread malaria, Zika virus, West Nile virus, and a brain infection called equine encephalitis, along with other diseases as well as heartworms in dogs, says Michael Sabourin, president of the Vermont Entomological Society. An animal health specialist for the state, Sabourin conducts vector surveys that identify ticks and mosquitoes.
Scientists refer to disease-carrying insects as vector species and, while there’s a limited number of them, many of these infections can be deadly. Fleas were a well-known vector for the bubonic plague, while kissing bugs are a vector for Chagas disease, a potentially life-threatening parasitic illness in humans, dogs, and other mammals, Sabourin says.
As the planet heats up, some of the creepy crawlers are able to survive milder winters or move up north. Warmer temperatures and a shorter snow season have spawned an increasing abundance of ticks in Maine, including the blacklegged tick (Ixodes scapularis), known to transmit Lyme disease, says Sean Birkel, an assistant professor in the Climate Change Institute and Cooperative Extension at the University of Maine.
Coupled with more frequent and heavier precipitation, rising temperatures bring a longer warm season that can also lead to a longer period of mosquito activity. “While other factors may be at play, climate change affects important underlying conditions that can, in turn, facilitate the spread of vector-borne disease,” Birkel says.
For example, if mosquitoes are finding fewer of their preferred food sources, they may bite humans more. Both male and female mosquitoes feed on sugar as part of their normal behavior, but if they aren’t eating their fill, they may become more bloodthirsty. One recent paper found that sugar-deprived Anopheles gambiae females go for larger blood meals to stay in good health and lay eggs. “More blood meals equals more chances to pick up and transmit a pathogen,” McDermott says, He adds that climate change could reduce the number of available plants to feed on. And while most mosquitoes are “generalist sugar-feeders” meaning that they will likely find alternatives, losing their favorite plants can make them hungrier for blood
Similar to the effect of losing plants, mosquitoes may get turned onto people if they lose their favorite animal species. For example, some studies found that Culex pipiens mosquitoes that transmit the West Nile virus feed primarily on birds in summer. But that changes in the fall, at least in some places. Because there are fewer birds around, C. pipiens switch to mammals, including humans. And if some disease-carrying insect species proliferate or increase their ranges, that increases chances for human infection, says McDermott. “A larger concern is that climate change could increase vector population sizes, making it more likely that people or animals would be bitten by an infected insect.”
Science Can Help Bring Back the Buzz
To help friendly insects thrive and keep the foes in check, scientists need better ways of trapping, counting, and monitoring insects. It’s not an easy job, but artificial intelligence and molecular methods can help. Ware’s lab uses various environmental DNA methods to monitor freshwater habitats. Molecular technologies hold much promise. The so-called DNA barcodes, in which species are identified using a short string of their genes, can now be used to identify birds, bees, moths and other creatures, and should be used on a larger scale, says Wagner, the University of Connecticut professor. “One day, something akin to Star Trek’s tricorder will soon be on sale down at the local science store.”
Scientists are also deploying artificial intelligence, or AI, to identify insects in agricultural systems and north latitudes where there are fewer bugs, Wagner says. For instance, some automated traps already use the wingbeat frequencies of mosquitoes to distinguish the harmless ones from the disease-carriers. But new technology and software are needed to further expand detection based on vision, sound, and odors.
“Because of their ubiquity, enormity of numbers, and seemingly boundless diversity, we desperately need to develop molecular and AI technologies that will allow us to automate sampling and identification,” says Wagner. “That would accelerate our ability to track insect populations, alert us to the presence of new disease vectors, exotic pest introductions, and unexpected declines.”