How Leqembi became the biggest news in Alzheimer’s disease in 40 years, and what comes next

How Leqembi became the biggest news in Alzheimer’s disease in 40 years, and what comes next

Betsy Groves, 73, with her granddaughter. Groves learned in 2021 that she has Alzheimer's disease. She hopes to take Leqembi, a drug approved by the FDA last week.

Betsy Groves

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.”

Jacqueline Detwiler-George
Jacqueline Detwiler is a contributing editor to Popular Mechanics and former host of The Most Useful Podcast Ever. She writes about science, adventure, travel, and technology. For stories, she has embedded with high school students in Indianapolis, jumped out of a plane with a member of the Red Bull Air Force, and travelled the country searching for the cure for cancer. Most recently, she trailed the Baltimore Police Department's Crime Scene Investigation team for a book for Simon & Schuster's Masters at Work series.
How thousands of first- and second-graders saved the world from a deadly disease

Although Jonas Salk has gone down in history for helping rid the world (almost) of polio, his revolutionary vaccine wouldn't have been possible without the world’s largest clinical trial – and the bravery of thousands of kids.

Exactly 67 years ago, in 1955, a group of scientists and reporters gathered at the University of Michigan and waited with bated breath for Dr. Thomas Francis Jr., director of the school’s Poliomyelitis Vaccine Evaluation Center, to approach the podium. The group had gathered to hear the news that seemingly everyone in the country had been anticipating for the past two years – whether the vaccine for poliomyelitis, developed by Francis’s former student Jonas Salk, was effective in preventing the disease.

Polio, at that point, had become a household name. As the highly contagious virus swept through the United States, cities closed their schools, movie theaters, swimming pools, and even churches to stop the spread. For most, polio presented as a mild illness, and was usually completely asymptomatic – but for an unlucky few, the virus took hold of the central nervous system and caused permanent paralysis of muscles in the legs, arms, and even people’s diaphragms, rendering the person unable to walk and breathe. It wasn’t uncommon to hear reports of people – mostly children – who fell sick with a flu-like virus and then, just days later, were relegated to spend the rest of their lives in an iron lung.

Keep Reading Keep Reading
Sarah Watts

Sarah Watts is a health and science writer based in Chicago.

Why you should (virtually) care

Virtual-first care, or V1C, could increase the quality of healthcare and make it more patient-centric by letting patients combine in-person visits with virtual options such as video for seeing their care providers.

(© Elnur/Fotolia)

As the pandemic turns endemic, healthcare providers have been eagerly urging patients to return to their offices to enjoy the benefits of in-person care.

But wait.

The last two years have forced all sorts of organizations to be nimble, adaptable and creative in how they work, and this includes healthcare providers’ efforts to maintain continuity of care under the most challenging of conditions. So before we go back to “business as usual,” don’t we owe it to those providers and ourselves to admit that business as usual did not work for most of the people the industry exists to help? If we’re going to embrace yet another period of change – periods that don’t happen often in our complex industry – shouldn’t we first stop and ask ourselves what we’re trying to achieve?

Certainly, COVID has shown that telehealth can be an invaluable tool, particularly for patients in rural and underserved communities that lack access to specialty care. It’s also become clear that many – though not all – healthcare encounters can be effectively conducted from afar. That said, the telehealth tactics that filled the gap during the pandemic were largely stitched together substitutes for existing visit-based workflows: with offices closed, patients scheduled video visits for help managing the side effects of their blood pressure medications or to see their endocrinologist for a quarterly check-in. Anyone whose children slogged through the last year or two of remote learning can tell you that simply virtualizing existing processes doesn’t necessarily improve the experience or the outcomes!

But what if our approach to post-pandemic healthcare came from a patient-driven perspective? We have a fleeting opportunity to advance a care model centered on convenient and equitable access that first prioritizes good outcomes, then selects approaches to care – and locations – tailored to each patient. Using the example of education, imagine how effective it would be if each student, regardless of their school district and aptitude, received such individualized attention.

Keep Reading Keep Reading
Jennifer C. Goldsack & Linette Demers
Jennifer C. Goldsack co-founded and serves as the CEO of the Digital Medicine Society (DiMe), a 501(c)(3) non-profit organization dedicated to advancing digital medicine to optimize human health. Jennifer’s research focuses on applied approaches to the safe, effective, and equitable use of digital technologies to improve health, healthcare, and health research. She is a member of the Roundtable on Genomics and Precision Health at the National Academies of Science, Engineering and Medicine and serves on the World Economic Forum Global Leadership Council on mental health. Previously, Jennifer spent several years at the Clinical Trials Transformation Initiative (CTTI), a public-private partnership co-founded by Duke University and the FDA. There, she led development and implementation of several projects within CTTI’s Digital Program and was the operational co-lead on the first randomized clinical trial using FDA’s Sentinel System. Jennifer spent five years working in research at the Hospital of the University of Pennsylvania, first in Outcomes Research in the Department of Surgery and later in the Department of Medicine. More recently, she helped launch the Value Institute, a pragmatic research and innovation center embedded in a large academic medical center in Delaware. Jennifer earned her master’s degree in chemistry from the University of Oxford, England, her masters in the history and sociology of medicine from the University of Pennsylvania, and her MBA from the George Washington University. Additionally, she is a certified Lean Six Sigma Green Belt and a Certified Professional in Healthcare Quality. Jennifer is a retired athlete, formerly a Pan American Games Champion, Olympian, and World Championship silver medalist. ___________________________________________________________________________ Linette Demers leads IMPACT, a DiMe initiative dedicated to advancing high value, evidence-based virtual first care for patients, healthcare providers, and payers. Previously, Linette was responsible for commercialization, entrepreneurship and capital formation programs at Life Science Washington and WINGS Angels. Her 20 year career in healthcare spans strategy, business development, and population health management in oncology care at Fred Hutch, and management consulting at Sg2. Linette holds a PhD in Chemistry and a BS in Health Economics and Outcomes Research.