Naked Mole Rats Defy Aging. One Scientist Has Dedicated Her Career to Finding Out How.
Rochelle "Shelley" Buffenstein has one of the world's largest, if not the largest, lab-dwelling colonies of the naked mole rat. (No one has done a worldwide tabulation, but she has 4,500 of them.) Buffenstein has spent decades studying the little subterranean-dwelling rodents. Over the years, she and her colleagues have uncovered one surprising discovery after another, which has led them to re-orient the whole field of anti-aging research.
Naked mole rats defy everything we thought we knew about aging. These strange little rodents from arid regions of Africa, such as Kenya, Ethiopia and Somalia, live up to ten times longer than their size would suggest. And unlike virtually every other animal, they don't lose physical or cognitive abilities with age, and even retain their fertility up until the end of life. They appear to have active defenses against the ravages of time, suggesting that aging may not be inevitable. Could these unusual creatures teach humans how to extend life and ameliorate aging?
Buffenstein, who is senior principle investigator at Calico Life Sciences, has dedicated her life to finding out. Her early interest in the animals of what is now Zimbabwe led to her current position as a cutting-edge anti-aging researcher at Calico, the Google-funded health venture launched in 2013. The notoriously secretive company is focused on untangling the mysteries of why animals and people age, and whether there are ways to slow or temporarily arrest the process.
The small, wrinkly animal, which lives in underground burrows in the hot, arid regions of Africa, is hardly the beauty queen of the mammalian kingdom. Furless, buck-toothed and tiny-eyed, the creatures look like they could use a good orthodontist, a protective suit of clothes and possibly, some spectacles to enhance their eyesight. But these rats more than make up for their unimpressive looks with their superlative ability to adapt to some of the most inhospitable conditions on earth.
Based on the usual rule that body size predicts lifespan, naked mole rats shouldn't live that long. After all, similarly-sized rodents like mice have a life expectancy of two years or less. But Buffenstein was one of the first scientists to recognize that naked mole rats live an extraordinarily long time, with her oldest animal approaching 39 years of age. In addition, they never become geriatric in the human sense, defying the common signs of aging — age-related diseases, cognitive decline and even menopause. In fact, the queens, or females that do all the breeding in a bee-like underground colony, remain fertile and give birth to healthy pups up until what would be considered very old age in humans. And the naked mole rat has other curious abilities, such as the ability to endure extreme low-oxygen, or hypoxic, conditions like those they encounter in their underground nests.
"One thing we've learned from these animals is that they stay healthy until the very end."
It's not that the naked mole rat isn't subject to the vicissitudes of life, or the normal wear and tear of biological processes. Over the years, Buffenstein and her colleagues have discovered that, while the process of oxidative stress — thought for 50 years to be the main cause of aging — occurs in the naked mole rat just as in any other animal, its damage does not accumulate with age. Oxidative stress occurs during normal cell metabolism when oxygen "free radicals" with one or more unpaired electrons wreak havoc on large cellular molecules, leaving microscopic debris in their wake that clogs up the gears of healthy cell function. Somehow, naked mole rats have an enhanced ability to clear out the damaged cells and molecules before they can set off the usual chain reaction of cell dysfunction and death, according to a 2013 paper in which Buffenstein is the lead author.
Oxidative stress is not the only factor known to be problematic in aging. Slowly accumulating damage to DNA typically leads to protein malfunction and improper folding. In humans and most other animals, these protein fragments can accumulate in cells and gum up the works. Only not so much in naked mole rats, which are able to maintain normal protein folding throughout their long life. After years of discoveries like these, Buffenstein has gradually reframed her focus from "what goes wrong to produce aging?" to "what goes right in the naked mole rat to help it defy the normal wear and tear of life?" Buffenstein's research suggests that the tiny mammals have a unique ability to somehow clear out damaged protein fragments and other toxic debris before they can cause disease and aging.
How She Got Here
Buffenstein ascribes her initial acquaintance with the naked mole rat to serendipity. Back in 1979, her postgraduate mentor Jenny Jarvis at the University of Cape Town in South Africa kept a small colony of rats in her office while studying the mechanisms that lead to the animals' unusual adaptive capabilities. It was Buffenstein's job to take care of them. Working with Jarvis, Buffenstein focused on understanding their unique adaptations to the extreme conditions of their natural habitat.
They studied the unusual behaviors regulating the rat colonies. For instance, they observed that designated "workers" dig the entire colony's underground tunnels and a single reproducing female breeds with only a small number of males. Buffenstein also examined how these animals are able to survive without the "sunshine hormone" — vitamin D — and their unusual modes of regulating their internal temperatures and converting food into energy. Though classified as mammals, the rodents simply don't conform to the mammalian handbook, having found ingenuous ways to alter their bodies and behavior that is fine-tuned to the scorching heat and aridity of their environment.
To escape the heat, they simply burrow underground and live in elaborate tunnels. To cope with the low-oxygen conditions underground, they slowed their metabolism and learned to live for extended periods of time in such hypoxic conditions that an ordinary animal would quickly suffocate. But it was slowly dawning on Buffenstein that the small creatures were exceptional in additional ways.
When Buffenstein got her first academic position at the University of Witwatersrand in Johannesburg, Jarvis said she could take some of the naked mole rats with her. When she did, Buffenstein noticed that the animals were living far longer than similarly sized rodents. "At that stage, they were about ten years old. Little did I know how long they would eventually show us they could live," she says.
In 1997, after accepting a position at the City College of New York, Buffenstein moved to the U.S. and took her rat colony with her. There she was able to pursue an evolving narrative about the humble naked mole rat that continued to defy expectations. As the years passed, it was becoming more and more evident that her observations could have major implications for aging research. Eventually, she took a position at the Barshop Institute for Aging and Longevity Studies in San Antonio, Texas.
One early observation of Buffenstein's suggested that the species most often used in aging research—mice, roundworms, fruit flies and yeast—have short lifespans and poor defenses against aging. These animals provide important insights into how aging works, and have revealed possible targets for intervention. But they don't show what goes right in apparently non-aging animals like the naked mole rat.
Buffenstein's years of studying the rats has laid the foundation for a whole new perspective in aging research.
"My hypothesis," she says, "is that naked mole rats are very good at removing damaged macromolecules and cells, thereby maintaining homeostasis and cell and tissue function. All the repair pathways examined by us and others in the field point to more efficient repair and more rapid responses to damaging agents." These include things like free radicals and radiation.
Buffenstein’s Legacy
Some researchers today are building on Buffenstein's foundational discoveries to home in on possible anti-aging mechanisms that lead to the extraordinary resilience of naked mole rats. University of Cambridge researcher and co-founder of the institution's Naked Mole-Rat Initiative, Ewan St. John Smith, is studying the animal's resistance to cancer.
In a 2020 paper published in Nature, Smith and his colleagues established that naked mole rats harbor cancer-causing genes, and these genes occasionally create cancer cells. But something in the rats shuts the multiplication process down before the cells can grow out of control and form tumors. Now, scientists want to know what mechanisms, exactly, are at play in preventing the cells from invading healthy tissues. Smith has hypothesized that the answer is somehow embedded in interactions in the cells' microenvironment.
He also thinks the animal's immune system could just be very effective at seeking out and destroying cancer cells. Several current cancer therapies work by boosting the body's immune system so it can attack and eliminate the toxic cells. It's possible that the naked mole rat's immune system naturally goes into hyper-drive when cancer cells appear, enabling it to nip the disease in the bud before tumors can form. A pharmacologist by training, Smith thinks that if there is some chemical mediator in the naked mole rat that supercharges its immune cells, perhaps that mediator can be synthesized in a drug to treat humans for cancer.
The naked mole rat's extreme tolerance to hypoxia could also play a role. "Interestingly," he says, "when cells become cancerous, they also become hypoxic, and naked mole rats are known to be very resistant to hypoxia.
He notes that a form of low-level hypoxia is also present in the bodies and brains of both aged mice and older humans. It's commonly seen in the brains of humans with Alzheimer's disease and other forms of age-related dementia. This suggests that hypoxia in humans — and in other mammals — may have a role to play in Alzheimer's and the aging process itself. Resistance to hypoxia could be why the naked mole rat, in Smith's words, "chugs along quite happily" in conditions that in humans are associated with disease and decline.
Smith cheerfully acknowledges his debt to Buffenstein for laying so much of the groundwork in a field rife with possible implications for anti-aging. "Shelley is amazing," he says. "Naked mole rats have a queen and I always refer to her as the queen of the naked mole rat world." In fact, Buffenstein gave Smith his first colony of rats, which he's since grown to about 150. "Some of them will still be around when I retire," he jokes.
Vera Gorbunova, a professor of biology and oncology at the University of Rochester who studies both longevity and cancer in naked mole rats, credits Buffenstein with getting others to study the animals for anti-aging purposes. Gorbunova believes that "cancer and aging go hand-in-hand" and that longer-lived animals have better, more accurate DNA repair.
Gorbunova is especially interested in the naked mole rat's ability to secrete a superabundance of a "super-sugar" molecule called hyaluronan, a ubiquitous additive to skin creams for its moisturizing effect. Gorbunova and others have observed that the presence of high concentrations of hyaluronan in the naked mole rat's extracellular matrix — the chemical-rich solution between cells — prevents the overcrowding of cells. This, perhaps, could be the key to the animal's ability to stop tumors from forming.
Hyaluronan is also present in the extracellular matrix of humans, but the naked mole rat molecule is more than five times larger than the versions found in humans or mice, and is thought to play a significant part in the animal's DNA repair. But just rubbing a cream containing hyaluronan over your skin won't stop cancer or aging. High concentrations of the substance in the extracellular matrix throughout your body would likely be needed.
Gorbunova notes that the naked mole rat offers a multitude of possibilities that could eventually lead to drugs to slow human aging. "I'm optimistic that there are many different strategies, because the naked mole rat likely has many processes going on that fight aging," she says. "I think that in a relatively short time, there will be bonafide treatments to test in animals. One thing we've learned from these animals is that they stay healthy until the very end."
So if naked mole rats don't become frail with age or develop age-related diseases, what does kill them? The answer, unfortunately, is usually other naked mole rats. Buffenstein has long noted that even though they live in highly cooperative colonies, they can be quite cantankerous when there's a disruption in the hierarchy, a sentiment echoed by Gorbunova. "Sometimes there are periods of peace and quiet, but if something happens to the queen, all hell breaks loose," she says. "If the queen is strong, everybody knows their place," but if the queen dies, the new queen is inevitably decided by violent competition.
To the casual observer, a strange, wrinkly rodent like the naked mole rat might seem to have little to teach us about ourselves, but Buffenstein is confident that her discoveries could have major implications for human longevity research. Today, at Calico's labs in San Francisco, she's focused entirely on the determining how anti-aging defense mechanisms in the rats could lead to similar defenses being stimulated or introduced in humans.
"The million-dollar question is, what are the mechanisms protecting against aging, and can these be translated into therapies to delay or abrogate human aging, too?"
Buffenstein fired up a new generation of scientists with multiple discoveries, especially the fundamental one that naked mole rats are subject to the same wear and tear over time as the rest of us, but somehow manage to reverse it. These days, the trailblazer is at work on untangling the molecular mechanisms involved in the animal's resistance to cardiac aging. On top of everything else, the small creature has a unique ability to fight off the scourge of heart disease, which is the leading cause of death in the industrialized world.
After all, the point is not to extend old age, but to slow down aging itself so that frailty and disability are compressed into a brief period after a long-extended period of vitality. By switching the focus from what goes wrong to mechanisms that defend against aging in the first place, the discoveries of Buffenstein and a new generation of researchers who are building on her groundbreaking research promise to be a driving force in the quest to extend not only life, but healthy, vigorous life in humans.
This article was first published by Leaps.org on June 23, 2021.
New tech for prison reform spreads to 11 states
A new non-profit called Recidiviz is using data technology to reduce the size of the U.S. criminal justice system. The bi-coastal company (SF and NYC) is currently working with 11 states to improve their systems and, so far, has helped remove nearly 69,000 people — ones left floundering in jail or on parole when they should have been released.
“The root cause is fragmentation,” says Clementine Jacoby, 31, a software engineer who worked at Google before co-founding Recidiviz in 2019. In the 1970s and 80s, the U.S. built a series of disconnected data systems, and this patchwork is still being used by criminal justice authorities today. It requires parole officers to manually calculate release dates, leading to errors in many cases. “[They] have done everything they need to do to earn their release, but they're still stuck in the system,” Jacoby says.
Recidiviz has built a platform that connects the different databases, with the goal of identifying people who are already qualified for release but remain behind bars or on supervision. “Think of Recidiviz like Google Maps,” says Jacoby, who worked on Maps when she was at the tech giant. Google Maps takes in data from different sources – satellite images, street maps, local business data — and organizes it into one easy view. “Recidiviz does something similar with criminal justice data,” Jacoby explains, “making it easy to identify people eligible to come home or to move to less intensive levels of supervision.”
People like Jacoby’s uncle. His experience with incarceration is what inspired her passion for criminal justice reform in the first place.
The problems are vast
The U.S. has the highest incarceration rate in the world — 2 million people according to the watchdog group, Prison Policy Initiative — at a cost of $182 billion a year. The numbers could be a lot lower if not for an array of problems including inaccurate sentencing calculations, flawed algorithms and parole violations laws.
Sentencing miscalculations
To determine eligibility for release, the current system requires corrections officers to check 21 different requirements spread across five different databases for each of the 90 to 100 people under their supervision. These manual calculations are time prohibitive, says Jacoby, and fall victim to human error.
In addition, Recidiviz found that policies aimed at helping to reduce the prison population don’t always work correctly. A key example is time off for good behavior laws that allow inmates to earn one day off for every 30 days of good behavior. Some states' data systems are built to calculate time off as one day per month of good behavior, rather than per day. Over the course of a decade-long sentence, Jacoby says these miscalculations can lead to a huge discrepancy in the calculated release data and the actual release date.
Algorithms
Commercial algorithm-based software systems for risk assessment continue to be widely used in the criminal justice system, even though a 2018 study published in Science Advances exposed their limitations. After the study went viral, it took three years for the Justice Department to issue a report on their own flawed algorithms used to reduce the federal prison population as part of the 2018 First Step Act. The program, it was determined, overestimated the risk of putting inmates of color into early-release programs.
Despite its name, Recidiviz does not build these types of algorithms for predicting recidivism, or whether someone will commit another crime after being released from prison. Rather, Jacoby says the company’s "descriptive analytics” approach is specifically intended to weed out incarceration inequalities and avoid algorithmic pitfalls.
Parole violation laws
Research shows that 350,000 people a year — about a quarter of the total prison population — are sent back not because they’ve committed another crime, but because they’ve broken a specific rule of their probation. “Things that wouldn't send you or I to prison, but would send someone on parole,” such as crossing county lines or being in the presence of alcohol when they shouldn’t be, are inflating the prison population, says Jacoby.
It’s personal for the co-founder and CEO
“I grew up with an uncle who went into the prison system,” Jacoby says. At 19, he was sentenced to ten years in prison for a non-violent crime. A few months after being released from jail, he was sent back for a non-violent parole violation.
“For my family, the fact that one in four prison admissions are driven not by a crime but by someone who's broken a rule on probation and parole was really profound because that happened to my uncle,” Jacoby says. The experience led her to begin studying criminal justice in high school, then college. She continued her dive into how the criminal justice system works as part of her Passion Project while at Google, a program that allows employees to spend 20 percent of their time on pro-bono work. Two colleagues whose family members had also been stuck in the system joined her.
As part of the project, Jacoby interviewed hundreds of people involved in the criminal justice system. “Those on the right, those on the left, agreed that bad data was slowing down reform,” she says. Their research brought them to North Dakota where they began to understand the root of the problem. The corrections department is making “huge, consequential decisions every day [without] … the data,” Jacoby says. In a new video by Recidiviz not yet released, Jacoby recounts her exchange with the state’s director of corrections who told her, “‘It’s not that we have the data and we just don’t know how to make it public; we don’t have the information you think we have.'"
A mock-up (with fake data) of the types of dashboards and insights that Recidiviz provides to state governments.
Recidiviz
As a software engineer, Jacoby says the comment made no sense to her — until she witnessed it first-hand. “We spent a lot of time driving around in cars with corrections directors and parole officers watching them use these incredibly taxing, frankly terrible, old data systems,” Jacoby says.
As they weeded through thousands of files — some computerized, some on paper — they unearthed the consequences of bad data: Hundreds of people in prison well past their release date and thousands more whose release from parole was delayed because of minor paperwork issues. They found individuals stuck in parole because they hadn’t checked one last item off their eligibility list — like simply failing to provide their parole officer with a paystub. And, even when parolees advocated for themselves, the archaic system made it difficult for their parole officers to confirm their eligibility, so they remained in the system. Jacoby and her team also unpacked specific policies that drive racial disparities — such as fines and fees.
The Solution
It’s more than a trivial technical challenge to bring the incomplete, fragmented data onto a 21st century data platform. It takes months for Recidiviz to sift through a state’s information systems to connect databases “with the goal of tracking a person all the way through their journey and find out what’s working for 18- to 25-year-old men, what’s working for new mothers,” explains Jacoby in the video.
TED Talk: How bad data traps people in the U.S. justice system
TED Fellow Clementine Jacoby's TED Talk went live on Jan. 13. It describes how we can fix bad data in the criminal justice system, "bringing thousands of people home, reducing costs and improving public safety along the way."
Clementine Jacoby • TED2022
Ojmarrh Mitchell, an associate professor in the School of Criminology and Criminal Justice at Arizona State University, who is not involved with the company, says what Recidiviz is doing is “remarkable.” His perspective goes beyond academic analysis. In his pre-academic years, Mitchell was a probation officer, working within the framework of the “well known, but invisible” information sharing issues that plague criminal justice departments. The flexibility of Recidiviz’s approach is what makes it especially innovative, he says. “They identify the specific gaps in each jurisdiction and tailor a solution for that jurisdiction.”
On the downside, the process used by Recidiviz is “a bit opaque,” Mitchell says, with few details available on how Recidiviz designs its tools and tracks outcomes. By sharing more information about how its actions lead to progress in a given jurisdiction, Recidiviz could help reformers in other places figure out which programs have the best potential to work well.
The eleven states in which Recidiviz is working include California, Colorado, Maine, Michigan, Missouri, Pennsylvania and Tennessee. And a pilot program launched last year in Idaho, if scaled nationally, with could reduce the number of people in the criminal justice system by a quarter of a million people, Jacoby says. As part of the pilot, rather than relying on manual calculations, Recidiviz is equipping leaders and the probation officers with actionable information with a few clicks of an app that Recidiviz built.
Mitchell is disappointed that there’s even the need for Recidiviz. “This is a problem that government agencies have a responsibility to address,” he says. “But they haven’t.” For one company to come along and fill such a large gap is “remarkable.”
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.”