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.
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.”
Podcast: The Friday Five weekly roundup in health research
Scientists have designed a phone app that could alert consumers to high levels of cancer-causing chemicals, Yale researchers revive organs in dead pigs, and more in this week's Friday Five.
The Friday Five covers five stories in health 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.
Listen to the Episode
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Covered in this week's Friday Five:
- A new blood test for cancer
- Patches of bacteria can use your sweat to power electronic devices
- Researchers revive organs of dead pigs
- Phone apps detects cancer-causing chemicals in foods
- Stem cells generate "synthetic placentas" in mice
Plus, an honorable mention for early research involving vitamin K and Alzheimer's
The limits of digital privacy are becoming clearer in the post-Dobbs era, as a wide range of data sources can reveal online and offline activities, including whether a woman seeks an abortion.
Since the recent reversal of Roe v. Wade — the landmark decision establishing a constitutional right to abortion — the vulnerabilities of reproductive health data and various other information stored on digital devices or shared through the Web have risen to the forefront.
Menstrual period tracking apps are an example of how technologies that collect information from users could be weaponized against abortions seekers. The apps, which help tens of millions of users in the U.S. predict when they’re ovulating, may provide evidence that leads to criminal prosecution in states with abortion bans, says Anton T. Dahbura, executive director of the Johns Hopkins University Information Security Institute. In states where abortion is outlawed, “it’s probably best to not use a period tracker,” he says.
Following the Dobbs v. Jackson ruling in late June that overturned Roe, even women who suffered a miscarriage could be suspected of having an abortion in some cases. While using these apps in anonymous mode may appear more secure, “data is notoriously difficult to perfectly anonymize,” Dahbura says. “Whether the data are stored on the user’s device or in the cloud, there are ways to connect that data to the user.”
Completely concealing one’s tracks in cyberspace poses enormous challenges. Digital forensics can take advantage of technology such as GPS apps, security cameras, license plate trackers, credit card transactions and bank records to reconstruct a person’s activities,” Dahbura says. “Abortion service providers are also in a world of risk for similar reasons.”
Practicing “good cyber hygiene” is essential. That’s particularly true in states where private citizens may be rewarded for reporting on women they suspect of having an abortion, such as Texas, which passed a so-called bounty hunter law last fall. To help guard against hacking, Dahbura suggests using strong passwords and two-factor authentication when possible while remaining on alert for phishing scams on email or texts.
Another option for safeguarding privacy is to avoid such apps entirely, but that choice will depend on an individual’s analysis of the risks and benefits, says Leah Fowler, research assistant professor at the University of Houston Law Center, Health Law & Policy Institute.
“These apps are popular because people find them helpful and convenient, so I hesitate to tell anyone to get rid of something they like without more concrete evidence of its nefarious uses,” she says. “I also hate the idea that asking anyone capable of becoming pregnant to opt out of all or part of the digital economy could ever be a viable solution. That’s an enormous policy failure. We have to do better than that.”
The potential universe of abortion-relevant data can include information from a variety of fitness and other biometric trackers, text and social media chat records, call details, purchase histories and medical insurance records.
Instead, Fowler recommends that concerned consumers read the terms of service and privacy policies of the apps they’re using. If some of the terms are unclear, she suggests emailing customer service with questions until the answers are satisfactory. It’s also wise for consumers to research products that meet their specific needs and find out whether other women have raised concerns about specific apps. Users interested in more privacy may want to switch to an app that stores data locally, meaning the data stays on your device, or does not use third-party tracking, so the app-maker is the only company with access to it, she says.
Period tracking apps can be useful for those on fertility journeys, making it easier to store information digitally than on paper charts. But users may want to factor in whether they live in a state with an anti-abortion stance and run the risk of legal issues due to a potential data breach, says Carmel Shachar, executive director of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School.
Consumers’ risks extend beyond period tracking apps in the post-Roe v. Wade era. “Anything that creates digital breadcrumbs to your reproductive choices and conduct could raise concerns — for example, googling ‘abortion providers near me’ or texting your best friend that you are pregnant but do not want to be,” Shachar says. Women also could incriminate themselves by bringing their phones, which may record geolocation data, to the clinic with them.
The potential universe of abortion-relevant data can include information from a variety of fitness and other biometric trackers, text and social media chat records, call details, purchase histories and medical insurance records, says Rebecca Wexler, faculty co-director of the Berkeley Center for Law & Technology. “These data sources can reveal a pregnant person’s decision to seek or obtain an abortion, as well as reveal a healthcare provider’s provision of abortion services and anyone else’s provision of abortion assistance,” she says.
In some situations, people or companies could inadvertently expose themselves to risk after posting on social media with offers of places for abortion seekers to stay after traveling from states with bans. They could be liable for aiding and abetting abortion. At this point, it’s unclear whether states that ban abortion will try to prosecute residents who seek abortions in other states without bans.
Another possibility is that a woman seeking an abortion will be prosecuted based not only on her phone’s data, but also on the data that law enforcement finds on someone else’s device or a shared computer. As a result, “people in one household may find themselves at odds with each other,” says K Royal, faculty fellow at the Center for Law, Science, and Innovation at Arizona State University’s Sandra Day O'Connor College of Law. “This is a very delicate situation.”
Individuals and corporate executives should research their options before leaving a digital footprint. “Guard your privacy carefully, whether you are seeking help or you are seeking to help someone,” Royal says. While she has come across recommendations from other experts who suggest carrying a second phone that is harder to link a person’s identity for certain online activities, “it’s not practical on a general basis.”
The privacy of this health data isn’t fully protected by the law because period trackers, texting services and other apps are not healthcare providers — and as a result, there’s no prohibition on sharing the information with a third party under the Health Insurance Portability and Accountability Act of 1996, says Florencia Marotta-Wurgler, a professor who specializes in online consumer contracts and data privacy at the NYU School of Law.
“So, as long as there is valid consent, then it’s fair game unless you say that it violates the reasonable expectations of consumers,” she says. “But this is pretty unchartered territory at the moment.”
As states implement laws granting anyone the power to report suspected or known pregnancies to law enforcement, anti-choice activists are purchasing reproductive health data from companies that make period apps, says Rebecca Herold, chief executive officer of Privacy & Security Brainiacs in Des Moines, Iowa, and a member of the Emerging Trends Working Group at ISACA, an association focused on information technology governance. They could also buy data on search histories and make it available in places like Texas for “bounty hunters” to find out which women have searched for information about abortions.
Some groups are creating their own apps described as providing general medical information on subjects such as pregnancy health. But they are “ultimately intended to ‘catch’ women” — to identify those who are probably pregnant and dissuade them from having an abortion, to launch harassment campaigns against them, or to report them to law enforcement, anti-choice groups and others in states where such prenatal medical care procedures are now restricted or prohibited, Herold says.
In addition to privacy concerns, the reversal of Roe v. Wade raises censorship issues. Facebook and Instagram have started to remove or flag content, particularly as it relates to providing the abortion pill, says Michael Kleinman, director of the Silicon Valley Initiative at Amnesty International USA, a global organization that promotes human rights.
Facebook and Instagram have rules that forbid private citizens from buying, selling or giving away pharmaceuticals, including the abortion pill, according to a social media post by a communications director for Meta, which owns both platforms. In the same post, though, the Meta official noted that the company’s enforcement of this rule has been “incorrect” in some cases.
“It’s terrifying to think that arbitrary decisions by these platforms can dramatically limit the ability of people to access critical reproductive rights information,” Kleinman says. However, he adds, “as it currently stands, the platforms make unilateral decisions about what reproductive rights information they allow and what information they take down.”