Amyloid plaques – the sticky protein deposits that choke brain cells – begin forming in the human brain up to two decades before the first symptom of Alzheimer’s disease ever appears. By the time a person walks into a doctor’s office struggling to recall a name or navigate a familiar route, that buildup has often been underway since their 40s or 50s. The window that researchers once considered unreachable is now the center of one of medicine’s most consequential experiments.
Two drugs already approved by the FDA to slow early Alzheimer’s are now being tested in a fundamentally different way: not to slow the disease after symptoms emerge, but to stop it from causing symptoms in the first place. The people enrolled in these trials aren’t patients. They show no signs of cognitive decline whatsoever. What they share is a measurable accumulation of amyloid in the brain – a biological warning sign that, until very recently, could only be confirmed through an expensive PET scan or an invasive spinal tap. For readers curious about how Alzheimer’s biomarker research has evolved, a recent analysis on supplement-based research puts the animal-model evidence in useful context.
The shift in strategy reflects decades of hard lessons. For years, the field focused almost entirely on treating Alzheimer’s after diagnosis. That approach yielded limited results. The reasoning behind these new prevention trials is direct: if amyloid drives the disease, and amyloid has been building for 20 years before symptoms appear, then the most logical time to intervene is before the damage becomes irreversible. Whether that logic holds in clinical practice is the question now being tested in thousands of cognitively healthy people around the world – and whether an Alzheimer’s prevention drug can truly work is the defining question of the moment.
The Drugs Already Changing Early Alzheimer’s Treatment
An estimated 7.2 million Americans age 65 and older are currently living with Alzheimer’s disease, according to the Alzheimer’s Association’s 2025 Facts and Figures report, with that number potentially reaching 13.8 million by 2060 without effective prevention or treatment breakthroughs.
Two drugs sit at the center of the current prevention push. Lecanemab, sold under the brand name Leqembi, received full FDA approval in July 2023 as the first therapy proven to slow cognitive decline by clearing amyloid from the brain. The drug is made by the pharmaceutical companies Eisai and Biogen, and its Phase 3 data came from the Clarity AD trial, published in The New England Journal of Medicine. In patients with early Alzheimer’s, lecanemab reduced brain amyloid levels and slowed cognitive decline by 27% over an 18-month period. The AHEAD 3-45 trial is now taking that same drug into a preclinical population – people with no symptoms at all.
The second drug, donanemab (brand name Kisunla), came next. Manufactured by Eli Lilly, it targets amyloid beta administered intravenously and received FDA approval in July 2024. Its Phase 3 clinical trial data, published in JAMA, was striking. Cognitive and functional decline slowed on all outcome measures: 35% on the iADRS scale, 37% on the CDR-SB, 32% on the ADAS-Cog13, and 40% on ADCS-iADL measures – all statistically significant results. Looking at the data another way, 47% of people on donanemab stayed stable on the CDR-SB over one year, compared with 29% on placebo.
Both approvals share an important boundary. Both lecanemab and donanemab are currently approved for early symptomatic Alzheimer’s disease – specifically, patients with mild cognitive impairment or mild dementia with confirmed amyloid pathology. The prevention trials now underway aim to move that window back considerably, to people who haven’t yet developed any symptoms at all.
The AHEAD 3-45 Trial: Testing an Alzheimer’s Prevention Drug Before Symptoms Begin
Alzheimer’s disease begins with a long asymptomatic or preclinical stage, during which amyloid beta accumulates for more than a decade before widespread neurodegeneration and clinical symptoms appear. The AHEAD 3-45 Study is testing whether intervention with lecanemab, initiated during this asymptomatic stage, can slow biomarker changes and cognitive decline.
The study is conducted as a public-private partnership of the Alzheimer’s Clinical Trial Consortium, funded by the National Institute on Aging, the NIH, and Eisai Inc., and consists of two parallel trials – called A3 and A45 – enrolling cognitively unimpaired adults ages 55 to 80, with specific dosing tailored to their baseline brain amyloid levels. The A3 arm targets people with intermediate amyloid accumulation (20 to 40 Centiloids, a unit used to quantify amyloid burden on PET imaging), while the A45 arm targets those with higher levels.
The primary aim of the A45 trial is to determine whether lecanemab is superior to placebo at slowing change from baseline on the Preclinical Alzheimer Cognitive Composite 5 (PACC5) at 216 weeks of treatment, while the A3 trial focuses on whether lecanemab can reduce brain amyloid accumulation as measured by amyloid PET. One arm is asking whether the drug preserves cognition; the other is asking whether it stops the biological process from advancing.
The AHEAD 3-45 Study is considered the first secondary prevention trial to use plasma-based biomarkers to improve the screening process, allowing researchers to identify suitable candidates and reduce the number of expensive PET scans required before randomization. Participants receive 55 intravenous infusions of lecanemab or placebo every four weeks over approximately four years.
TRAILBLAZER-ALZ 3: Donanemab’s Prevention Gamble
Eli Lilly’s parallel effort is TRAILBLAZER-ALZ 3, and its design reflects a different set of scientific bets. The trial is a parallel-group, double-blind, placebo-controlled, event-based Phase 3 study of donanemab in cognitively unimpaired participants with evidence of Alzheimer’s pathology, conducted in the United States and Japan.
The study measures time to clinical progression over 332 weeks – that’s roughly six and a half years of follow-up, underscoring how long researchers expect to wait before the biological risk translates into measurable cognitive change. Enrollment in TRAILBLAZER-ALZ 3 finished in August 2024, meaning the trial is now fully underway with its complete cohort of participants. Eligibility screening relied on a plasma phosphorylated tau-217 (p-tau217) blood assay to detect Alzheimer’s pathology, with a decentralized trial design used to enhance enrollment across a wider range of geographic locations.
The decentralized approach is more than a logistical convenience. Decentralized trials offer flexibility typically limited in traditional trial design, which can increase geographic and ethnic diversity in trial populations, improve participant engagement and retention, and reduce overall trial cost.
Unlike AHEAD 3-45, TRAILBLAZER-ALZ 3 included some participants who scored 0.5 on the CDR – meaning a small fraction had the mildest detectable cognitive impairment. About one-third of the cohort carried that CDR 0.5 designation, though researchers noted the methodology captured an earlier Alzheimer’s population than the previous donanemab Phase 3 treatment trial.
What the Blood Test Changes
Both prevention trials depend on the ability to identify amyloid buildup in living people – quickly, affordably, and at scale. That problem has recently gotten much closer to being solved. On May 16, 2025, the FDA cleared the first blood test to aid in diagnosing Alzheimer’s disease: the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio, approved for adults aged 55 and older who are exhibiting signs and symptoms of the disease. In its clinical study, 91.7% of individuals with positive results had the presence of amyloid plaques confirmed by PET scan or CSF test, and 97.3% of individuals with negative results had a negative amyloid PET scan or CSF test result.
Research published in 2026 extended that finding further, showing that pTau217 blood levels can detect early Alzheimer’s disease progression even before amyloid PET scans show abnormalities. That capability matters enormously for prevention trials. If a blood draw can flag people who are on a trajectory toward Alzheimer’s before their PET scan would catch it, screening becomes dramatically more accessible – and clinical trials can identify at-risk individuals far earlier.
About 83% of Americans surveyed by the Alzheimer’s Association said they were worried to some degree about developing Alzheimer’s, and 4 out of 5 said they’d want a diagnosis before symptoms disrupted their daily lives and that they’d be willing to take a blood test to detect early biomarkers if one were available.
Understanding the Safety Profile
These drugs are not without risk, and the prevention context introduces a particular ethical consideration: participants in AHEAD 3-45 and TRAILBLAZER-ALZ 3 feel completely healthy. The most frequently reported adverse events are amyloid-related imaging abnormalities, or ARIA – changes visible on brain MRI that reflect the drug’s interaction with amyloid in blood vessel walls.
For lecanemab, treatment reduced brain amyloid levels and slowed cognitive decline, but was associated with adverse effects including infusion reactions and amyloid-related imaging abnormalities. In the Clarity AD trial, ARIA involving vasogenic edema (fluid accumulation in brain tissue, called ARIA-E) occurred in 12.6% of treated participants, while ARIA involving microhemorrhages (small bleeds, called ARIA-H) occurred in 17.3%. For donanemab, ARIA-E occurred in 19.8% to 24.4% of treated participants, and ARIA-H occurred in 27.2% to 31.3%, according to data from the TRAILBLAZER-ALZ program reviewed by NeurologyLive. Most cases were mild to moderate and detected on routine MRI monitoring rather than through noticeable symptoms, but serious cases have occurred.
Genetic risk adds another layer of complexity. Carriers of the APOE ε4 allele – a gene variant that significantly elevates a person’s biological risk of Alzheimer’s – face the highest risk for ARIA, with homozygous carriers (those who carry two copies of the variant) showing a 41.7% rate of ARIA-E in the donanemab trials. Because APOE ε4 is also associated with higher amyloid accumulation and therefore higher likelihood of being enrolled in prevention trials, this overlap in risk profile will require careful management as these studies continue.
Researchers are tracking safety outcomes as closely as cognitive ones. A 2025 review of anti-amyloid monoclonal antibodies found that the drugs consistently demonstrated robust amyloid clearance alongside modest slowing of clinical decline – confirming that the biological mechanism works, while also confirming that the clinical benefit, though real, is currently measured in degrees rather than in dramatic reversals of disease course.
The Bigger Pipeline Picture
AHEAD 3-45 and TRAILBLAZER-ALZ 3 are the highest-profile prevention trials active right now, but they sit inside a much larger ecosystem of research. NeurologyLive noted that the FDA’s clearance of the Lumipulse G test represents a major step in expanding access to AD diagnostics, and the broader 2026 Alzheimer’s clinical trial pipeline now comprises 158 agents in 192 active trials, with nearly three-quarters being disease-modifying programs. That scale reflects a field that has moved past asking whether amyloid-targeting therapies can work at all – the Phase 3 data on lecanemab and donanemab answered that – and is now asking how early they need to be given, and to whom.
The TRAILBLAZER-ALZ 3 study is specifically designed to measure time to clinical progression in preclinical Alzheimer’s disease, making it an event-based trial rather than a change-from-baseline trial. Instead of comparing average cognitive scores between groups, researchers are tracking how long it takes for each participant to cross a meaningful clinical threshold. In the earlier Phase 3 donanemab treatment trial, participants treated with the drug had an additional 7.5 months on average before reaching the same level of cognitive and functional decline as those on placebo – and if the prevention trial extends that gap even further, the implications for disease burden at population scale would be substantial.
Read More: Early Alzheimer’s Warning Signs
What This Means for You
The drugs being tested in these trials are not yet approved for prevention. Until AHEAD 3-45 and TRAILBLAZER-ALZ 3 report their primary outcomes – which will take several more years – no Alzheimer’s prevention drug exists in the clinical sense. Lecanemab and donanemab are approved only for people who already show early symptoms of Alzheimer’s with confirmed amyloid in the brain.
If you are over 55, have a family history of Alzheimer’s, or carry the APOE ε4 gene variant, the most immediately actionable step is to ask your doctor about the Lumipulse G pTau217 blood test, which is now FDA-cleared for symptomatic adults aged 55 and older. The test is intended for patients presenting at a specialized care setting with signs and symptoms of cognitive decline, and results must be interpreted alongside other clinical information. For asymptomatic adults, the test is not yet standard of care, but the prevention trials above are actively enrolling cognitively normal participants – and eligibility screening for both AHEAD 3-45 and TRAILBLAZER-ALZ 3 begins with a blood draw, not a PET scan.
The science is moving faster than it ever has. Two drugs that didn’t exist in approved form five years ago are now being tested in people who have no symptoms at all. Whether that strategy can prevent dementia rather than just slow it is the defining question of this decade in neurology – and within the next few years, we’ll have the first real data to answer it.
Disclaimer: This information is not intended to be a substitute for professional medical advice, diagnosis, or treatment and is for information only. Always seek the advice of your physician or another qualified health provider with any questions about your medical condition and/or current medication. Do not disregard professional medical advice or delay seeking advice or treatment because of something you have read here.
AI Disclaimer: This article was created with the assistance of AI tools and reviewed by a human editor.