While there are plenty of things that teenagers worry about, dementia isn’t normally one of them. Yet one new major Alzheimer’s drug trial is recruiting people as young as 18 to answer what may be the most pressing question facing the field: Can the ravages of the disease be prevented by identifying those on track to get it and treating them up to 10 years before they show symptoms?
The recent arrival of drugs that slow the cognitive decline of Alzheimer’s in many people is a welcome breakthrough, but so far their efficacy has only been demonstrated in people with mild symptoms. By the time patients are diagnosed, their brains have already undergone extensive changes. But growing evidence suggests that taking the drugs well before that damage has occurred could significantly slow the disease and possibly even stop it in its tracks.
“Now we have drugs that can slow the disease by 30 percent or so in people with symptoms, but that’s not good enough,” says Reisa Sperling, a neurologist who heads the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital in Boston. “We want to get to 100 percent, and that means preventing people from getting to the symptomatic stages.”
Earlier and earlier
In medicine, treating a disease when it is causing pathological changes in the body, but hasn’t yet progressed far enough to cause clinical symptoms, is known as secondary prevention. (Primary prevention is heading off a disease before there is any pathology, and tertiary prevention is managing symptomatic disease to slow the worsening of symptoms.) Secondary prevention has been essential to medicine’s triumphs in reducing the risks of death and disability for those with early heart disease or diabetes. Doctors don’t wait for someone to have a heart attack before prescribing a cholesterol-lowering statin or for someone to suffer artery or kidney damage before putting them on metformin to control blood sugar.
In 2023, the results of trials of lecanemab (brand name Leqembi) and donanemab on Alzheimer’s patients with mild cognitive impairment suggested that medicine may now have the tools to bring secondary prevention to bear on the disease. Both drugs are monoclonal antibodies that target the hardened clumps of protein called amyloid plaque that form in the brains of Alzheimer’s patients.
Although much is still unknown about the mechanisms of Alzheimer’s, there is little question now that the buildup of plaque precedes symptoms by many years. In the lecanemab and donanemab trials, the earlier patients were along the long road to plaque buildup, the better the drugs did in removing most of the plaque and slowing cognitive decline. “It’s when you remove nearly all the plaque with one of these drugs that you see the real benefits in terms of symptoms,” says Randall Bateman, a physician and professor of neurology at Washington University School of Medicine.
Because patients with even mild symptoms already have a large buildup of plaque, testing the notion that plaque-fighting drugs can be more effective earlier in the buildup process means enlisting presymptomatic patients for trials. “Studies are moving toward people who are just at the borderline for being positive for plaque and treating them to try to keep them from accumulating more of it and from having symptoms,” says Susan Abushakra, a physician and researcher who is vice president of clinical development and medical affairs at Alzheimer’s-focused biotech company Alzheon in Framingham, Mass.
Three past trials have already focused on presymptomatic patients. One was the A4 study run by Brigham and Women’s Sperling, which ended in 2020 after six years. It looked at the effect of the anti-plaque drug solanezumab on patients without cognitive impairment, but in whom PET imaging revealed some buildup of plaque. The other was the DIAN-TU study, headed by Washington University’s Bateman, which studied the effect of solanezumab or gantenerumab, another anti-plaque drug, on patients who carry a rare familial genetic mutation that puts them at extreme likelihood of developing Alzheimer’s and starting cognitive decline in their 30s, 40s or 50s.
The third trial was the Alzheimer’s Prevention Initiative ADAD Trial, which also studied presymptomatic carriers of the familial early-onset mutation. ADAD took place in Colombia, and used the Genentech amyloid-clearing drug crenezumab. The eight-year trial ended in 2021. “When we first started talking about doing a prevention trial in 2008, people thought we were nuts for wanting to put healthy people in that long a study,” recalls Eric Reiman, a physician and neuroscientist at the University of Arizona and Arizona State University and executive director of the Banner Alzheimer’s Institute, which ran the ADAD study.
The A4 and DIAN-TU studies received funding from GHR Foundation, which was also involved as lead philanthropic funder in the other trials as well. “Philanthropy can play a distinct catalytic role in this kind of visionary research,” says GHR CEO Amy Goldman. Drug companies may hesitate to plunge into risky trials because shareholders want more certainty; and NIH and other public funding, while substantial, sometimes comes with administrative overhead. Philanthropies can change the game. “We’re willing to take risks and provide the seed money to get a trial started, and we can be patient with long-term, complex trials with a high potential for failure, especially with trials like these where there’s also high potential for impact.” Goldman says. Ultimately, the trials are typically funded by public-private philanthropic partnerships.
The three trials failed to find significant benefit to patients. But scientists don’t interpret the findings as counter to the idea that anti-amyloid drugs, if given early enough, could potentially prevent cognitive decline. The drugs tested in all three trials work by different mechanisms than the newer drugs lecanemab and donanemab and never reached the same stages of regulatory approval. The newer drugs are now regarded as much more promising. In fact, the DIAN-TU trial is being extended with lecanemab.
Joey Guidone/Theispot
Armed with the newer drugs, new trials on presymptomatic patients with confirmed plaque buildup are underway. One is AHEAD 3-45, also run by Sperling, which will test the effect of lecanemab on patients as young as 55 and as old as 80. The four-year-long trial will actually comprise two sister trials, A3 and A45. A3 is a phase 2 trial that will focus on people with lower levels of brain amyloid, while A45 is a phase 3 trial in which subjects have higher levels. In addition, A3 aims to measure the progression in amyloid while A45 will focus more on the onset of cognitive impairment. “All the data are pointing in the direction of getting better results by treating patients earlier in the disease, but now we need to prove it,” says Sperling.
Another presymptomatic study is the TRAILBLAZER-ALZ 3, which will test donanemab on subjects with amyloid plaque but no signs of cognitive impairment. One relatively unique feature of the trial is that it will try to minimize the inconvenience to subjects, who would normally have to go to select hospitals to have brain scans and periodic in-person cognitive assessments. TRAILBLAZER-ALZ 3, in contrast, will rely primarily on easily administered blood tests and on telephone-based cognitive assessments. Reducing the subject burden in these ways is expected to make it much easier in Alzheimer’s trials to enroll larger numbers of patients and to reduce the dropout rate. Like the AHEAD 3-45 trial, TRAILBLAZER-ALZ 3 will run through 2027.
A third study—an additional branch of the DIAN-TU trials—is aiming for a still-earlier intervention. That trial will test the effects of lecanemab on 230 subjects as young as 18. Because those patients carry the family genetic mutation that makes it almost certain they will develop symptoms of Alzheimer’s by middle age and most likely by the time they are in their late 30s, the trial provides a chance to see the effects of treating the disease two decades or more ahead of the first symptoms.
Technically, this very-early-intervention DIAN-TU trial is addressing primary rather than secondary prevention, because the brains of these young subjects don’t yet show signs of Alzheimer’s pathology. But the results are likely to apply to secondary prevention, as well as to patients without the mutation, says Bateman. “In every study we know of, the results have lined up between people with the mutation and people with the sporadic form of the disease,” he says, referring to the more common, later-in-life course of Alzheimer’s. “It’s highly likely the results of this trial will inform all of Alzheimer’s.”
Banner’s Reiman is also planning a new ADAD trial using either lecanemab or donanemab. “Now that those drugs have been studied in amyloid-positive people with mild cognitive impairment, the fact that they work means they’re almost certainly going to work in cognitively unimpaired people,” he contends.
Faster trials, better treatments
One reason that effective Alzheimer’s treatments have been so long in coming is that the slow course of the disease, and in particular the long lag between the early buildup of plaque and clinical symptoms, has made drug trials especially slow and costly. Identifying presymptomatic patients with plaque buildup has required PET scans or sampling spinal fluid, and determining whether a drug works on them has required watching them for years for symptoms that can be hard to assess.
But the prospects of drug trials on presymptomatic people may be transforming, experts say. Plaque buildup can now be confirmed with blood tests, making it much easier and inexpensive to screen potential trial subjects. In a February 2024 paper in Lancet Neurology, Reiman and four colleagues argued that secondary prevention therapies could be approved for widespread use in three to five years and that blood biomarker tests will be able to be used to determine who is eligible.
In addition to new anti-plaque drugs, a second strategy is picking up momentum in the field: tackling the tangles of tau protein that form in the brains of Alzheimer’s patients around the time symptoms emerge. One theory gaining prominence in the field is that the long buildup of plaque eventually triggers or accelerates the formation of tangles, and it is the tangles that primarily cause the emergence and worsening of cognitive decline. Several anti-tau drugs are now in trials. Yet another new arm of the DIAN-TU trial will be testing three of them with Alzheimer’s patients, in some cases combining them with anti-plaque drugs. Sperling, too, is planning a trial where patients will be treated with both anti-amyloid and anti-tau drugs.
Sperling notes that side effects of the anti-plaque drugs—particularly the risk of small-stroke-like brain bleeds that show up in a small percentage of patients—remain a concern. So does the cost of treatment, currently running more than $2,000 a month for lecanemab, plus the cost of administering the drug intravenously and closely monitoring patients who receive it. But she’s confident the costs will come down—injectable versions of the drug, which are much easier to administer, are already in the works—and that further research will allow reducing the risks of side effects. “We need to be able to predict and prevent those events,” she says.
Noninvasive therapies are also being developed to preserve brain health. For instance, Cognito Therapeutics is developing a headset that uses sensory stimulation (light and sound) to provoke gamma-wave activity in the brain, which plays a role in learning and memory and is altered in Alzheimer’s patients.
Before founding Cognito in 2016, Ed Boyden and Li-Huei Tsai of MIT confirmed in preclinical models that provoking gamma-wave activity with sensory stimulation can slow the rate of Alzheimer’s disease progression. In later phase 2 trials, patients experienced a 69 percent slowing of brain volume loss and a 77 percent slowing of functional decline compared to a control group. A recent MRI study of the trial participants suggests that the device’s combined visual and auditory stimulation reduces white matter atrophy and myelin loss, which help modulate neuronal network function. (Cognito is funded by in part by Morningside, a sponsor of this special edition, Alzheimer’s Drug Discovery Foundation, Founders X, and other firms.) The findings suggest that nondrug interventions may also play a role in secondary prevention of Alzheimer’s.
This article is part of The New Age of Alzheimer’s, a special report on the advances fueling hope for ending this devastating disease.