Amyloid immunotherapies took 20 years to reach the clinic. Scientists are testing new types of therapies they hope could deliver stronger benefits and fewer side effects

On a spring day in 2011, neuroscientist Cynthia Lemere stood nervously before scientists gathered to appraise the world’s latest research—including hers—at a conference on immune strategies for treating Alzheimer’s disease. Advancing her presentation slides to show stained brain tissue from a recent set of mouse experiments, Lemere circled the pointer around the reddish-brown clumps: protein fragments called amyloid beta that form plaques, a hallmark of the disease. In Lemere’s experiments, mice that received antibody treatment accumulated fewer amyloid plaques than animals receiving placebo.

Some in the audience were skeptical. As Lemere recalls, when she finished her presentation one prominent researcher rose and proclaimed: “It’s not a real thing. It’s a biochemical artifact.”

What that researcher dismissed, others pursued. Lemere and colleagues at Brigham and Women’s Hospital in Boston have studied this form of amyloid beta since the 1990s; so have researchers in Japan and Germany. Now, the rogue protein is center stage: A drug (donanemab) that targets the molecule recently showed clear benefits in a large clinical study of people with mild Alzheimer’s disease.   

Donanemab’s success follows another Alzheimer’s drug, lecanemab (brand name Leqembi), which hit the market in January, and aducanumab (brand name Aduhelm), which got a nod from the U.S. Food and Drug Administration in 2021 after a controversial review. (Aducanumab was withdrawn from the market in 2024.) These are the first new Alzheimer’s treatments since 2003, and the only ones to impede the disease’s progression; earlier drugs only eased symptoms.

The new therapies are revitalizing Alzheimer’s research and renewing hope for millions of families touched by this devastating disease. Yet these treatments carry some risk and a formidable price tag. Translating them from controlled studies to clinical use will require diagnostics that are more scalable and accessible, as well as new training to equip physicians to recognize early-stage disease and decide who is eligible for treatment.

MOLECULAR UNDERPINNINGS

Alzheimer’s is the most common cause of dementia. It afflicts nearly 7 million people in the United States and more than 30 million worldwide. Older drugs—including donepezil, galantamine and rivastigmine—work by prolonging the activity of key chemical messengers in the brain. This enhancement of nerve cell communication offers a temporary boost but does not get at the disease’s molecular roots.

The newest drugs do. They are the long-awaited fruit of the amyloid hypothesis, the theory that identifies amyloid buildup as an essential trigger that disrupts neural circuits, causing mental decline and other signs of dementia decades later. This theory has driven much of the Alzheimer’s disease research and drug development since the 1990s.

Creating drugs to slow this progression requires a deep understanding of how the culprit molecules form and how they become a threat. Before amyloid clumps into disease-associated plaques, it floats in the blood as harmless proteins. Day by day, decade after decade, these amyloid beta peptides are churned out and cleared out, like scores of other proteins processed in the brain as part of normal metabolism.

At some point, though, things go awry. Amyloid collects and forms clumps in the brain, eventually killing nerve cells and making it hard for people to remember things and manage everyday tasks such as paying bills and getting dressed. “Watching a neurodegenerative disease cause the slow decline of a loved one is sad, worrisome and exhausting,” says Lemere. She lost two aunts to a related condition, Lewy body dementia, and says that “definitely had an impact on my desire to keep working in this field.”

To study the progression of Alzheimer’s, Lemere and colleagues use laboratory mice that are engineered to mimic key pathological manifestations of the human disease. One example: the plaques stained reddish-brown on Lemere’s conference presentation slides. 

Each clump represents amyloid beta, but these peptides are anything but identical. Some exist alone as monomers. Others assemble into menacing structures called fibrils, or as intermediate-sized oligomers, which many researchers consider to be the most toxic to nerve cells. Plaques can act as a reservoir for these smaller, toxic species. 

What’s more, individual peptides differ in length and shape and sometimes morph further through chemical reactions, as shown in scores of biochemical studies. One variant—a ring-shaped molecule called pyroglutamate amyloid beta (pyroglu Aß) is especially nasty. In lab studies decades ago, it seemed sturdier and stickier than other amyloid peptides and hurt nerve cells even at tiny concentrations. 

These observations were later confirmed in therapeutics tested on mice and ultimately in clinical trials of Alzheimer’s patients—but it has taken decades to capture attention from the scientific community.

AN INTRIGUING CULPRIT

Initial descriptions of pyroglu Aß appeared in the biomedical literature as early as 1985. Interest grew as multiple labs published follow-up papers confirming the presence of this unusual protein in autopsy tissue from Alzheimer’s patients. In some brain specimens Lemere analyzed in the 1990s as a Ph.D. student, pyroglu Aß appeared as a dominant species. 

In those analyses—when Lemere noticed that pyroGlu showed up well in some samples but less so in others—it seemed to depend on how the tissues were processed. When specimens sat in fixative solution for longer than a few hours, pyroglu Aß was faint or undetectable, she says. 

Methodological challenges like that plagued the field for years, fueling claims that pyroglu Aß was a biochemical artifact. 

There was another problem with pyroglu Aß: No one could explain how it was formed. Then, in 2000, a doctoral student in Germany studying diabetes made a surprising discovery. Stephan Schilling was investigating how a pancreatic hormone resists degradation in the bloodstream.

He found that the hormone was chemically altered by an enzyme that adds pyroglutamate and that the same enzyme can add pyroglutamate to many other proteins—including amyloid beta. 

During his postdoc, Schilling reported in 2008 that inhibiting this enzyme, called glutaminyl cyclase, curbs amyloid buildup and improves cognition in mice and fruit flies that model Alzheimer’s disease.

An inhibitor of the enzyme has been developed by Vivoryon Therapeutics AG, a German precision medicine company, and was recently tested in a clinical trial of people with mild Alzheimer’s disease, says Schilling, who is now a professor at Anhalt University of Applied Sciences and serves on Vivoryon’s scientific advisory board. (The inhibitor did not prove effective at slowing cognitive decline, the company announced in March.)

While developing the enzyme inhibitor, company researchers started pursuing another strategy—immunizing mice with antibodies against pyroglu Aß. The rationale was that if pyroglu Aß is found in plaques, then targeting it with antibodies could lower brain amyloid and slow cognitive decline. Schilling and Lemere joined forces in 2008, testing pyroglu Aß antibodies made by Probiodrug AG, which later became Vivoryon, on Lemere’s brain tissue samples and Alzheimer’s mouse models.

AMYLOID IMMUNOTHERAPY

By then, amyloid had emerged as a prime focus for Alzheimer’s drug development. The first strategy to reach clinical testing was active immunotherapy: vaccinate with amyloid beta peptide to stimulate an immune response to remove amyloid deposits. 

This approach worked in mice and was further studied in people with mild to moderate Alzheimer’s disease. But investigators stopped that trial in 2001 after 6 percent of participants developed brain inflammation, presumably resulting from an autoimmune response to injection with a naturally occurring protein.

To avoid those harmful effects, some Alzheimer’s trials turned to passive immunotherapy—injecting antibodies directly into the patient rather than stimulating the patient’s body to make them.

Scientists at Lilly Research Laboratories in Indianapolis developed an antibody that binds soluble amyloid beta, thinking this could shift the equilibrium to prevent neurotoxic aggregates from forming. The antibody looked impressive in Alzheimer’s mice, reversing memory deficits even as amyloid piled up in their brains. But when Eli Lilly created a humanized version of this antibody and moved it into clinical trials, the antibody, solanezumab, failed to help patients with mild to moderate symptoms who enrolled in two late-stage, placebo-controlled studies. Meanwhile, bapineuzumab, an antibody that recognizes both soluble and plaque amyloid, also failed in a large phase 3 trial; Johnson & Johnson and Pfizer decided in 2012 to discontinue this drug. 

Although the drugs failed to help patients, the two studies did mark the first use in Alzheimer’s research of an important new tool:  positron emission tomography (PET) brain scans that measure amyloid load in the brains of live patients. PET revealed that nearly a quarter of participants in the solanezumab and bapineuzumab trials did not in fact have Alzheimer’s—their scans showed no brain amyloid—so the tested drugs could not have helped them. And though the Alz-heimer’s antibody trials were failing to identify new drugs, collectively the trials were teaching researchers something valuable: experimental treatments seem to work better when started earlier in the disease process.

Soon Eli Lilly took another shot: It enrolled 2,129 patients in an 18-month trial, in which they would receive monthly infusions of either the drug solanezumab or a placebo. To qualify for that study, participants had to test positive for amyloid, by brain scan or spinal fluid analysis. Yet even with the tightened criteria, the company reported in late 2016 that treated patients showed only a hint of improvement, relative to the placebo group. “It did move the needle, but not enough to be a medicine,” says Eric Siemers, who started a consulting business in 2017 after 19 years directing Eli Lilly’s Alzheimer’s disease program. “That was a big disappointment.”

And although passive immunotherapy has proved safer by avoiding the brain inflammation that halted the 2001 active immunotherapy trial, antibody infusions still raise concern. A subset of participants develop brain swelling and microbleeds—amyloid-related imaging abnormalities (ARIA), which show up on magnetic resonance imaging (MRI) scans. Some patients experience symptoms—typically headache, confusion or nausea—and three participants in clinical trials with ARIA have died, so patients with ARIA symptoms must be monitored. But most ARIA cases are asymptomatic, transient and resolve with corticosteroids.

DESPAIR AND DETERMINATION

Alzheimer’s drug development is high stakes and high risk. More than 300 interventions—79 of them amyloid-related—have entered clinical testing, and 99 percent of experimental therapies have performed no better than placebo in clinical trials, according to the therapeutics database at Alzforum, a web resource for researchers studying Alzheimer’s and related disorders. 

Given these tough odds, companies hedge their bets. While testing antibodies, some also pursued other amyloid strategies—for example, a pill that reduces amyloid beta levels by blocking the activity of an enzyme called BACE1 that is required to produce it. “A lot of people were convinced that these BACE inhibitors were going to be the solution,” Siemers says. 

But four large studies of such drugs showed no drug-placebo difference in Alzheimer’s patients; in fact, treated participants actually got a bit worse. For some researchers, the failed trial of Merck’s BACE inhibitor in 2019 was a breaking point. It prompted a reevaluation in the field. “To be blunt, amyloid-beta lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward,” Mayo Clinic neurologist David Knopman wrote in a 2019 commentary shortly after the failed trial.

For Schilling, such declarations instilled determination to continue the research. “I wanted to show all these people that [pyroglu Aß] is a concept that is viable and that can be used to develop a treatment,” he says. Meanwhile, Lemere’s team used the pyroglu Aß antibody developed by Schilling’s Probiodrug colleagues to treat Alzheimer’s in mice. Reporting in a February 2012 paper, “we found that we were clearing regular amyloid beta as well,” she says.  

A team from Eli Lilly published similar findings with their pyroglu Aß antibody later that year and ultimately advanced it into clinical testing before the smaller Probiodrug team could. In spring 2021, the company reported that this drug, donanemab, slowed cognitive decline in a phase 2 trial of 257 participants with early Alzheimer’s disease. 

NEW HOPE

That was a “turning point,” says Knopman, whose enthusiasm for amyloid-lowering treatments had waned with past failures of BACE inhibitors and immunotherapy trials. More success followed. In 2022 Eisai and Biogen reported that participants with early-stage Alzheimer’s who were treated with another amyloid antibody, lecanemab (Leqembi), declined 27 percent more slowly than the placebo group in a large 18-month trial. And in summer 2023, Eli Lilly reported that donanemab slowed cognitive worsening by 35 percent in amyloid-positive mild Alzheimer’s patients who also had low to moderate levels of another protein, tau.

The latest results suggest that patients lose function five months later than they would have otherwise during 18 months of treatment, according to a recent analysis by researchers at Pentara, a clinical trials consulting firm. This could preserve their ability to drive or delay their need to move into a nursing home, says CEO Suzanne Hendrix, a statistician who helped Eisai design a key scoring metric for the pivotal trial leading to lecanemab’s FDA approval.

As the newest Alzheimer’s drugs begin the challenging transition from research trials to real-world use, researchers are testing new types of therapies that they hope can achieve stronger benefits with fewer side effects. 

Eli Lilly itself is working on a newer pyroglutamate antibody that eases some of donanemab’s side effects and seems to clear plaques faster, according to early data reported this spring. And researchers at Vivoryon, working with Schilling and Lemere, are trying to re-engineer their pyroglu Aß antibody so it cannot activate the immune reactions underlying ARIA. “It’s important to try to find ways to mitigate ARIA,” says Lemere. “Before I retire, I have to figure this out.”

Meanwhile, several companies are still pursuing active immunotherapy by creating safer amyloid beta vaccines that could one day be deployed to prevent disease, especially once blood tests replace the much costlier brain scans to detect preclinical Alzheimer’s. 

In another decade or so, some researchers think such blood panels could become routine—and they would check not just amyloid and tau but also other proteins that are associated with dementia or neurodegeneration. Screening would start around age 65 or 70. “If my amyloid beta and tau are high, maybe I get on a drug that can lower those and prevent me from getting Alzheimer’s, and in someone else it might be a different brain protein,” says neurologist Gil Rabinovici, who directs the Alzheimer’s Disease Research Center at the University of California, San Francisco. “These panels are going to tell us what is going on in the brain and what we might be at risk for developing over time.”