Lecanemab works differently from older Alzheimer’s drugs in a fundamental way: it targets the underlying biology of the disease rather than compensating for its symptoms. Every Alzheimer’s medication approved before lecanemab — donepezil, rivastigmine, galantamine, and memantine — was designed to make the brain work better despite the damage, not to slow the damage itself. Lecanemab, sold under the brand name Leqembi, is the first FDA-approved therapy that actually modifies the course of the disease by clearing amyloid from the brain. To understand what that distinction means in practice, consider a patient in the early stages of Alzheimer’s who starts donepezil.
Their memory may stabilize or even improve modestly for a period of months. But the amyloid plaques and tau tangles destroying their neurons are still accumulating, unchecked, in the background. Lecanemab takes a different approach: it uses the immune system to identify and remove the most toxic forms of amyloid, potentially slowing that destruction at its source. In the pivotal Phase 3 clinical trial, patients on lecanemab experienced 27% less cognitive decline compared to placebo over 18 months. This article explains the science behind that difference, what the clinical evidence shows, where lecanemab falls short, and what it means for patients and families navigating Alzheimer’s care today.
Table of Contents
- What Are Older Alzheimer’s Drugs Actually Doing — and Why Don’t They Change the Disease?
- How Lecanemab Targets Amyloid — and Why Soluble Protofibrils Matter
- What the Clarity AD Trial Results Actually Mean for Patients
- FDA Approval and What It Means Compared to Earlier Drug Approvals
- ARIA — The Safety Risk That Older Drugs Never Carried
- Who Can and Cannot Use Lecanemab — and Why Stage Matters
- What Lecanemab Signals About the Future of Alzheimer’s Treatment
- Conclusion
- Frequently Asked Questions
What Are Older Alzheimer’s Drugs Actually Doing — and Why Don’t They Change the Disease?
The drugs that dominated Alzheimer’s treatment for two decades fall into two pharmacological categories. Cholinesterase inhibitors — donepezil, rivastigmine, and galantamine — work by preventing the breakdown of acetylcholine, a neurotransmitter critical for memory and learning. In Alzheimer’s, the neurons that produce acetylcholine are among the first to be damaged, so these drugs compensate by stretching the supply of whatever remains. Memantine works differently, blocking NMDA receptors to regulate glutamate activity and protect neurons from overstimulation. Neither drug class has any effect on amyloid plaques, tau tangles, or the underlying neurodegenerative process.
The analogy that physicians sometimes use is instructive: these drugs are like turning up the volume on a radio with a broken speaker. You might hear the music more clearly for a while, but the speaker is still deteriorating. Cholinesterase inhibitors typically produce modest cognitive benefits for six to twelve months in many patients, and their effects wane as neuronal loss progresses. They remain useful and are still widely prescribed — particularly for moderate to severe Alzheimer’s, where lecanemab is not approved — but they were never described, even by their developers, as doing anything to slow the disease. That fundamental limitation defined Alzheimer’s pharmacology for decades.
How Lecanemab Targets Amyloid — and Why Soluble Protofibrils Matter
Lecanemab is a humanized IgG1 monoclonal antibody, meaning it is an engineered immune protein designed to recognize a specific molecular target with high precision. Its primary target is soluble amyloid-beta protofibrils — an intermediate form of amyloid that sits between the earliest monomers and the dense, insoluble plaques that have long been the focus of Alzheimer’s research. This distinction matters enormously. Protofibrils are not just another form of amyloid; evidence suggests they are the most neurotoxic form, capable of disrupting synaptic function and triggering inflammatory cascades before they ever consolidate into visible plaques. Earlier anti-amyloid antibodies largely missed this target. Drugs like aducanumab focused predominantly on insoluble plaques, which may be less biologically active and harder to clear efficiently.
Lecanemab attacks amyloid through two pathways simultaneously — targeting soluble protofibrils directly while also clearing insoluble plaque deposits. This dual action appears to produce broader amyloid reduction. In the Clarity AD trial, patients on the approved dose of 10 mg/kg every two weeks showed a statistically significant reduction in brain amyloid plaque from baseline through week 79, while the placebo group showed no reduction. Lecanemab’s mechanism also appears to reduce downstream tau pathology, which is significant because tau accumulation is closely linked to the actual pattern of cognitive decline. However, a critical limitation applies here: lecanemab’s amyloid-clearing mechanism only produces meaningful benefit in patients who still have living neurons worth protecting. That is why the drug is approved only for early-stage Alzheimer’s — mild cognitive impairment or mild dementia — where amyloid burden is present but neuronal loss has not yet become severe. Patients with moderate or advanced disease are not candidates, and using the drug at later stages is not expected to offer meaningful benefit regardless of how effectively it clears amyloid.
What the Clarity AD Trial Results Actually Mean for Patients
The Phase 3 Clarity AD trial enrolled 1,795 participants with early Alzheimer’s confirmed by amyloid PET or csf biomarkers. Over 18 months, patients receiving lecanemab declined 27% more slowly than those receiving placebo on the primary cognitive and functional scale used. The trial’s p-value was less than 0.0001, indicating the result was not a statistical artifact. That 27% slowing translates, on average, to approximately a six-month delay in symptom progression — meaning a patient on lecanemab might have roughly six additional months of functioning at a given level compared to someone not on the drug. That number requires honest context.
Six months is not nothing — particularly for a patient in early-stage disease who values independence in daily activities — but it is also not a cure, and the absolute differences between groups, while statistically significant, are modest in magnitude. The clinical significance of the benefit has been debated among neurologists, with some viewing it as a meaningful first step and others noting that the functional improvements may be difficult for patients to perceive in daily life. What is not debatable is that patients treated at the earliest identifiable stages showed the greatest benefit, which is consistent with the biological logic: the less neuronal damage already present, the more there is to protect. Longer-term data has been accumulating. At the 2025 Alzheimer’s Association International Conference, four-year follow-up data showed patients maintained continued benefit with prolonged treatment. Separately, data presented at the 2025 CTAD Conference confirmed lecanemab’s pharmacological effect on neurotoxic amyloid-beta protofibrils in cerebrospinal fluid, providing biological evidence that the drug is doing what it is designed to do even at the molecular level in living patients.
FDA Approval and What It Means Compared to Earlier Drug Approvals
Lecanemab’s regulatory path reflected the evidentiary standards the FDA had been wrestling with for years in Alzheimer’s drug development. On January 6, 2023, the FDA granted lecanemab accelerated approval — a pathway used when a drug demonstrates an effect on a surrogate endpoint reasonably likely to predict clinical benefit. In this case, the surrogate endpoint was amyloid reduction. The accelerated approval pathway had been controversial in Alzheimer’s drug development following the approval of aducanumab in 2021, which the FDA approved over the objections of its advisory committee on amyloid-reduction grounds without demonstrated cognitive benefit. Lecanemab avoided that controversy because it had already demonstrated cognitive benefit in clinical trials.
In July 2023, the FDA converted lecanemab’s approval to a full traditional approval — a relatively rapid conversion — based on the demonstrated clinical benefit from the Clarity AD trial. This made lecanemab the first Alzheimer’s therapy to receive traditional approval on the basis of actually slowing cognitive decline, a regulatory milestone that older symptomatic drugs never needed to achieve because they were approved on different grounds. The tradeoff between lecanemab and older drugs on the practical side is stark. Donepezil is a once-daily pill, widely available as a generic, inexpensive, and requires no special monitoring beyond routine follow-up. Lecanemab requires intravenous infusion every two weeks, ongoing MRI monitoring for brain safety events, confirmation of amyloid positivity before treatment, and specialist access that remains unevenly distributed. For many patients — especially those without convenient access to academic medical centers — these logistics are genuine barriers, not theoretical ones.
ARIA — The Safety Risk That Older Drugs Never Carried
The most significant safety concern with lecanemab is ARIA, or amyloid-related imaging abnormalities. ARIA encompasses two related phenomena: ARIA-E, which involves brain edema or swelling, and ARIA-H, which involves small hemorrhages or hemosiderin deposits. These occur because the immune response that clears amyloid from brain tissue and blood vessel walls can cause localized inflammation and vascular disruption. In the Clarity AD trial, ARIA of any kind occurred in approximately 21% of lecanemab-treated patients, compared to about 9% in the placebo group. Most ARIA events were asymptomatic and detected only on MRI, but symptomatic cases did occur, and three deaths in the trial were associated with ARIA in context of anticoagulant use. Older drugs — donepezil, memantine, and the other cholinesterase inhibitors — carry no risk of ARIA whatsoever. Their side effect profiles are real (nausea, bradycardia, dizziness for cholinesterase inhibitors; confusion and dizziness for memantine at higher doses) but they do not involve brain swelling or hemorrhage.
For patients on blood thinners, or those with a history of microhemorrhages, ARIA risk with lecanemab is elevated and warrants particularly careful evaluation. Genetic factors also matter: patients who carry the APOE4 allele, which is both a risk factor for Alzheimer’s and common in the early-onset population most likely to seek lecanemab treatment, face higher rates of ARIA. This does not automatically exclude them from treatment but does require informed discussion of the risk-benefit profile. The requirement for ongoing MRI monitoring is a practical consequence of ARIA risk that older drugs never imposed. Patients on lecanemab typically undergo MRI scans before starting treatment, after the first several infusions, and periodically throughout, with additional scans if symptoms develop. Radiologists and neurologists interpreting these scans need familiarity with ARIA appearances to avoid misclassification. This monitoring infrastructure adds cost and complexity, and at centers not experienced with the drug, it can create uncertainty.
Who Can and Cannot Use Lecanemab — and Why Stage Matters
Lecanemab’s approval is restricted to early-stage Alzheimer’s disease: specifically, mild cognitive impairment (MCI) due to Alzheimer’s disease, or mild Alzheimer’s dementia. Patients must have confirmed amyloid pathology — established through either a PET scan or cerebrospinal fluid testing — because the drug is only relevant for amyloid-driven disease, and not all patients presenting with cognitive decline have Alzheimer’s pathology. This is a meaningful difference from older drugs, which could be prescribed based on clinical diagnosis alone without biomarker confirmation.
The practical implication is that patients with moderate or severe Alzheimer’s — the population for whom donepezil and memantine were most commonly used for years — are not eligible for lecanemab. In that population, the amyloid has already done extensive damage, and the remaining clinical question is managing symptoms and maintaining quality of life, which is exactly what the older drugs are designed to address. In this sense, lecanemab and the older drugs are not strictly competing — they serve different patient populations at different disease stages, and a patient who received donepezil for years and then progressed to moderate disease would not become a candidate for lecanemab at that point.
What Lecanemab Signals About the Future of Alzheimer’s Treatment
Lecanemab’s approval represents a proof of concept that targeting the underlying biology of Alzheimer’s — rather than compensating for its symptoms — can produce measurable clinical benefit. That is not a small thing after decades of failed trials and withdrawn drugs. It has validated the amyloid hypothesis in a new form, shifted attention to the importance of early intervention and biomarker-confirmed diagnosis, and opened the door to combination approaches that might target both amyloid and tau simultaneously.
Ongoing research is exploring whether lecanemab could be used in truly pre-symptomatic individuals — people with elevated amyloid on PET but no cognitive symptoms yet — which would be a further shift in how Alzheimer’s prevention is conceptualized. Other anti-amyloid antibodies, and drugs targeting different aspects of Alzheimer’s biology, are moving through clinical pipelines. The landscape in five years may look substantially different from today, but lecanemab represents the first confirmed step into a new era of treatment rather than the last word in it.
Conclusion
Lecanemab differs from older Alzheimer’s drugs at the most fundamental level: it targets and removes the toxic amyloid deposits that drive the disease, while older drugs merely compensate for the neurological damage those deposits cause. That distinction — between disease modification and symptom management — is not a marketing slogan. It reflects a real difference in mechanism, clinical evidence, and what the treatment can and cannot accomplish. The 27% slowing of cognitive decline in the Clarity AD trial, confirmed by four years of follow-up data and molecular evidence from cerebrospinal fluid studies, represents the first validated pharmacological intervention to change Alzheimer’s trajectory.
At the same time, lecanemab is not a cure, its benefits are modest in absolute terms, and it comes with genuine risks — particularly ARIA — that older drugs do not carry. It is appropriate only for patients with early-stage, biomarker-confirmed Alzheimer’s disease, and it requires logistical infrastructure that remains out of reach for many. For patients and families evaluating options, the honest picture is one of meaningful but incremental progress: the first drug that actually fights the disease, at the cost of real complexity, real risk, and real limitations. Older drugs remain relevant and important, particularly in later disease stages. Lecanemab and its successors are best understood not as replacements for everything that came before, but as the beginning of a different kind of treatment approach — one aimed, finally, at the disease itself.
Frequently Asked Questions
Is lecanemab a cure for Alzheimer’s disease?
No. Lecanemab slows the progression of early Alzheimer’s disease but does not stop or reverse it. In clinical trials, it reduced the rate of cognitive decline by approximately 27% over 18 months, which translates to roughly a six-month delay in symptom progression. It does not restore lost function or halt the disease entirely.
Can patients already taking donepezil switch to lecanemab?
Not as a direct substitution — lecanemab is only approved for early-stage disease, and the two drugs address different aspects of Alzheimer’s. Some patients may be candidates for lecanemab while also continuing a cholinesterase inhibitor, but eligibility depends on disease stage and amyloid confirmation, not current medication status. A specialist evaluation is required.
Who is eligible for lecanemab treatment?
Patients with mild cognitive impairment or mild Alzheimer’s dementia who have confirmed amyloid pathology through PET imaging or cerebrospinal fluid testing. Patients with moderate or severe Alzheimer’s, or those without confirmed amyloid burden, are not eligible under the current FDA approval.
What is ARIA and how serious is it?
ARIA refers to amyloid-related imaging abnormalities — brain swelling (ARIA-E) or small hemorrhages (ARIA-H) that can occur as a side effect of anti-amyloid therapy. In the Clarity AD trial, ARIA of any kind occurred in about 21% of lecanemab-treated patients. Most cases were asymptomatic and detected only on MRI. Serious or symptomatic ARIA is less common but can occur, particularly in patients on anticoagulants or those carrying the APOE4 gene variant.
Why does lecanemab target protofibrils rather than plaques?
Amyloid-beta protofibrils — soluble, intermediate forms of amyloid — are believed to be the most neurotoxic form of amyloid, causing synaptic disruption and inflammation before they consolidate into insoluble plaques. By targeting protofibrils specifically, lecanemab attacks amyloid at its most dangerous stage. It also clears insoluble plaques, giving it a dual-pathway mechanism.
How is lecanemab administered compared to older Alzheimer’s drugs?
Lecanemab is given as an intravenous infusion every two weeks and requires regular MRI monitoring for ARIA. Older drugs like donepezil and memantine are oral pills taken daily, require no infusion infrastructure, and have no MRI monitoring requirements. The logistical difference is significant and affects access for many patients.
