Donanemab and lecanemab are the two most significant anti-amyloid antibody treatments to emerge from Alzheimer’s research in recent years, and while they share a common mechanism, their clinical profiles differ in meaningful ways. The short answer: lecanemab (brand name Leqembi) received traditional FDA approval in July 2023 and is currently the more accessible option, while donanemab (brand name Kisunla) received FDA approval in July 2024 and showed slightly stronger slowing of cognitive decline in its pivotal trial — but with a dosing schedule designed to stop once amyloid is cleared. Neither drug stops Alzheimer’s disease; both modestly slow its progression in early stages, with real but limited functional benefit.
In the TRAILBLAZER-ALZ 2 trial, donanemab slowed cognitive and functional decline by approximately 35% in participants with low-to-medium tau burden, compared to lecanemab’s 27% slowing of clinical decline in the CLARITY AD trial. That difference sounds significant, but the trials used different measurement tools and different patient populations, making direct comparison complicated. Importantly, both drugs carry serious risks, particularly brain swelling and bleeding known as ARIA (amyloid-related imaging abnormalities). This article examines the two drugs side by side — their mechanisms, trial results, safety profiles, dosing differences, who qualifies, and what families navigating an early Alzheimer’s diagnosis should realistically expect.
Table of Contents
- How Do Donanemab and Lecanemab Target Alzheimer’s Differently?
- What Do the Clinical Trial Results Actually Show?
- How Do the Safety Profiles and ARIA Risks Compare?
- Dosing, Duration, and the Practical Differences for Patients
- Who Qualifies, and What Are the Access Barriers?
- What Do Specialists Think About Choosing Between Them?
- What Comes Next in Anti-Amyloid Therapy?
- Conclusion
- Frequently Asked Questions
How Do Donanemab and Lecanemab Target Alzheimer’s Differently?
Both donanemab and lecanemab are monoclonal antibodies that work by targeting and clearing amyloid plaques from the brain. However, they bind to different forms of amyloid-beta. Lecanemab preferentially targets soluble amyloid-beta protofibrils — aggregates that are still forming — whereas donanemab targets a modified, insoluble form of amyloid called pyroglutamate amyloid-beta, which is found specifically in established plaques. This distinction matters because it shapes how quickly each drug clears amyloid and, in donanemab’s case, made it possible to define a stopping point.
Think of it this way: lecanemab is aiming at amyloid in an earlier, more mobile state, while donanemab is targeting the hardened deposits already locked into brain tissue. In the TRAILBLAZER-ALZ 2 trial, roughly 40% of donanemab participants achieved amyloid clearance to below detectable threshold levels by 12 months, and about 72% reached that threshold by 18 months. Lecanemab’s trials showed amyloid reduction as well, but the treatment design does not include a built-in stopping point — patients continue indefinitely. This difference in biological targeting has practical downstream consequences for treatment duration, cost, and monitoring burden.
What Do the Clinical Trial Results Actually Show?
The CLARITY AD trial for lecanemab enrolled approximately 1,795 participants and measured decline using the CDR-SB (Clinical Dementia Rating Sum of Boxes), finding a 27% slowing of decline over 18 months compared to placebo. The TRAILBLAZER-ALZ 2 trial for donanemab enrolled approximately 1,736 participants and reported a 35% slowing of decline on the iADRS (integrated Alzheimer’s Disease Rating Scale) in the combined population, and 35% on the CDR-SB in those with low-to-medium tau. Both results were statistically significant. However, the real-world meaning of these numbers deserves scrutiny. On a scale that runs from 0 to 18 points (CDR-SB), the difference between treated and placebo groups at 18 months was roughly 0.45 points for lecanemab and around 0.7 points for donanemab (in the low-to-medium tau group).
These are measurable but subtle differences in day-to-day functioning — not dramatic reversals. A person might retain the ability to manage a simple task or hold a conversation slightly longer, but the disease continues to progress. If a family expects either drug to restore meaningful independence or halt decline, they will likely be disappointed. The drugs are appropriate only for early-stage Alzheimer’s, and both trials excluded patients with moderate or severe dementia. Importantly, donanemab’s results in participants with high tau burden — indicating more advanced pathology — showed no statistically significant benefit. This is a critical warning: by the time significant tau tangles are present alongside amyloid, these drugs appear to lose their efficacy, making early detection and intervention essential to accessing any benefit at all.
How Do the Safety Profiles and ARIA Risks Compare?
Both drugs cause ARIA — a class of side effects that includes brain swelling (ARIA-E) and microbleeds (ARIA-H). These are detected on MRI and range from asymptomatic to serious, rarely including seizures, neurological changes, or death. The rates differ between the two drugs in ways families should understand clearly. In the CLARITY AD trial, lecanemab was associated with ARIA-E in about 12.6% of participants and ARIA-H in about 17.3%. In the TRAILBLAZER-ALZ 2 trial, donanemab showed ARIA-E in approximately 24% and ARIA-H in approximately 31.4%. On the surface, this suggests donanemab carries a higher ARIA burden. However, the majority of these events were asymptomatic and detected only through protocol MRI scans.
Symptomatic ARIA occurred in roughly 6.1% of donanemab patients compared to approximately 2.8% for lecanemab. Three deaths in the donanemab trial were considered possibly related to treatment ARIA; one death in the lecanemab trial was similarly attributed. These are small numbers but real risks that require informed consent and careful consideration. APOE4 gene carriers face elevated ARIA risk with both drugs. Individuals who carry two copies of the APOE4 allele (homozygous) face particularly high rates of serious ARIA and were, in some cases, excluded or warned against participation in trials. Eli Lilly’s prescribing information for donanemab specifically notes that APOE4 homozygotes should be counseled carefully about risk-benefit balance before starting treatment. Genetic testing for APOE status has therefore become a practical part of the pre-treatment workup for both medications.
Dosing, Duration, and the Practical Differences for Patients
Lecanemab is administered as an intravenous infusion every two weeks, indefinitely. There is no defined stopping point — the assumption is that amyloid will re-accumulate if treatment stops. This means patients and caregivers face a continuing commitment to biweekly clinic visits, ongoing MRI monitoring, and sustained insurance authorization. For families already managing caregiver logistics, this is a nontrivial burden. Donanemab is given as a monthly intravenous infusion — a less frequent schedule — and, uniquely, treatment can be stopped once amyloid clears to a defined threshold.
In TRAILBLAZER-ALZ 2, participants who cleared amyloid stopped active treatment and were monitored; their outcomes through the trial period were comparable to those who continued. This is a meaningful practical advantage: many patients completed a finite course of treatment (median around 12 months for some) rather than committing to indefinite infusions. The tradeoff is uncertainty about long-term durability. It is not yet fully understood how long the benefit persists after stopping, or whether amyloid accumulates again at a clinically relevant pace after cessation. On cost, both drugs carry list prices in the range of $26,000 to $32,000 per year, though actual out-of-pocket costs depend heavily on insurance coverage, Medicare status, and manufacturer assistance programs. Donanemab’s finite treatment course could in theory result in lower cumulative cost for patients who clear amyloid quickly, though infusion center fees, MRI monitoring, and associated care costs are substantial regardless of which drug is used.
Who Qualifies, and What Are the Access Barriers?
Both drugs are approved only for patients with early symptomatic Alzheimer’s disease — specifically mild cognitive impairment (MCI) due to Alzheimer’s or mild Alzheimer’s dementia — who have confirmed amyloid pathology. Confirmation requires either a PET scan to visualize amyloid in the brain or a cerebrospinal fluid (CSF) analysis. Both tests add time, cost, and in the case of lumbar puncture, some procedural discomfort. Blood-based amyloid biomarkers are improving rapidly, and some major academic centers are beginning to use them in conjunction with clinical assessment, but as of 2025-2026, PET or CSF confirmation remains the standard for treatment eligibility. Access barriers are substantial and unevenly distributed. Medicare covers lecanemab with standard coverage following its traditional FDA approval, but coverage with Evidence Development (CED) restrictions created significant friction in 2023.
Donanemab’s Medicare coverage landscape has evolved similarly. The required infrastructure — amyloid confirmation, specialist diagnosis, infusion center capacity, and regular MRI monitoring — tends to be concentrated in urban academic medical centers. Patients in rural areas, or those without strong specialist access, frequently find these treatments logistically out of reach even when they qualify medically. A warning worth emphasizing: patients with certain medical histories are categorically excluded from these treatments. Those with recent strokes, significant pre-existing microbleeds, or conditions requiring anticoagulation therapy face substantially elevated bleeding risk with either drug and are generally not candidates. Physicians at memory care clinics are increasingly developing careful screening protocols, but referring clinicians in primary care settings may not always be aware of these contraindications.
What Do Specialists Think About Choosing Between Them?
In practice, most neurologists do not yet have a strong evidence-based reason to choose one drug over the other for an individual patient — the trials were not head-to-head, the patient populations differed, and the measurement tools varied. The choice is often driven by availability, insurance coverage, patient and caregiver preference regarding dosing frequency, and local infusion center experience.
For a patient who wants a defined, potentially finite course of treatment and can tolerate monthly infusions, donanemab’s stopping-point design has appeal. For a patient already enrolled at a center experienced with lecanemab or whose insurer covers it more smoothly, lecanemab may be the practical first choice. One neurologist at a large academic memory clinic described the current decision-making as “mostly logistical rather than clinical” — a candid acknowledgment that both drugs occupy similar therapeutic territory.
What Comes Next in Anti-Amyloid Therapy?
The landscape is moving quickly. Researchers are increasingly focused on combination approaches — targeting both amyloid and tau simultaneously — since tau pathology appears to correlate more closely with the actual severity of cognitive decline than amyloid alone. Trials combining anti-amyloid antibodies with anti-tau agents are underway, as are studies examining whether earlier intervention (in the pre-symptomatic phase) could yield larger benefits.
Subcutaneous formulations of lecanemab are in development and could eventually replace IV infusions for some patients, dramatically reducing the logistical burden. Blood-based biomarkers, particularly phospho-tau 217, are advancing toward clinical use and may eventually replace or supplement PET scans for both diagnosis and treatment monitoring. The donanemab and lecanemab approvals represent the beginning of disease-modifying therapy in Alzheimer’s, not its peak — but the pace of progress over the next decade will determine whether these early treatments are remembered as meaningful milestones or merely as proof-of-concept.
Conclusion
Donanemab and lecanemab represent genuine, if modest, advances in Alzheimer’s treatment — the first drugs to receive traditional FDA approval by demonstrating actual slowing of disease progression rather than symptom management alone. Donanemab showed slightly stronger efficacy in its trial population with lower tau burden and offers a distinct advantage in its finite, stopping-point treatment design. Lecanemab has a longer track record in clinical use, a biweekly rather than monthly infusion schedule, and in many regions a more established coverage and access pathway.
Neither drug is dramatically superior to the other, and neither is appropriate for moderate or advanced Alzheimer’s. For families facing an early-stage diagnosis, the most important steps are seeking evaluation at a memory care center with experience in these therapies, pursuing biomarker confirmation promptly (amyloid status, APOE genotyping), and having an honest conversation with a neurologist about realistic expectations. Both drugs slow decline — they do not stop it, and they do not reverse what has already been lost. Understanding that boundary clearly, while still pursuing treatment for those who qualify, is the most constructive way to approach this difficult decision.
Frequently Asked Questions
Can donanemab or lecanemab be used in moderate or severe Alzheimer’s?
No. Both drugs are approved only for early-stage disease — mild cognitive impairment or mild dementia due to Alzheimer’s with confirmed amyloid. There is no evidence of benefit in moderate or severe stages, and both trials excluded these patients.
Do I need a genetic test before starting either drug?
APOE4 genotyping is strongly recommended before starting either drug, though it is not always required. Patients who are APOE4 homozygous face significantly elevated ARIA risk and need thorough counseling before proceeding.
How long does donanemab treatment last?
Treatment with donanemab can stop once amyloid clears to below a defined threshold on PET imaging. In clinical trials, many patients reached this point between 6 and 18 months. However, not all patients clear amyloid within the treatment window.
Why can’t I just take both drugs together?
Combination therapy with two anti-amyloid antibodies has not been studied and is not approved. The cumulative ARIA risk would likely be prohibitive, and there is no clinical evidence to support this approach.
Are these drugs covered by Medicare?
Yes, both drugs have Medicare coverage, though coverage pathways have evolved and continue to be clarified. Out-of-pocket costs, supplemental coverage, and local formulary decisions vary significantly. Manufacturer patient assistance programs exist for both.
How often are MRI scans required during treatment?
Both drugs require regular MRI monitoring for ARIA, particularly in the first months of treatment. Typical protocols involve MRI scans before treatment, then at intervals following initial infusions, with additional scans if symptoms suggesting ARIA develop.
