Understanding how lecanemab works to remove amyloid plaques represents a significant shift in Alzheimer’s disease treatment, moving from symptom management to directly targeting the underlying disease pathology. For decades, researchers have known that sticky protein clumps called amyloid-beta plaques accumulate in the brains of people with Alzheimer’s disease, but developing a treatment capable of safely and effectively clearing these plaques proved extraordinarily challenging. Lecanemab, marketed under the brand name Leqembi, became the first amyloid-targeting therapy to receive traditional FDA approval in July 2023, marking a watershed moment in neurology. The significance of this medication extends beyond its clinical effects.
For patients, caregivers, and the broader dementia community, lecanemab offers something that has been notably absent in Alzheimer’s care: a treatment that addresses the disease itself rather than merely masking symptoms. While cholinesterase inhibitors and memantine help manage cognitive symptoms, they do nothing to slow the relentless progression of neurodegeneration. Lecanemab works differently, binding to and neutralizing the toxic protein aggregates that many scientists believe drive the disease process. This article examines the mechanism by which lecanemab removes amyloid plaques from the brain, the clinical evidence supporting its use, practical considerations for patients and families, and what this therapy means for the future of Alzheimer’s treatment. By the end, readers will have a thorough understanding of how this monoclonal antibody functions at the molecular level, what to expect from treatment, and how to have informed conversations with healthcare providers about whether this therapy might be appropriate.
Table of Contents
- What Exactly Are Amyloid Plaques and Why Does Lecanemab Target Them?
- The Molecular Mechanism Behind Lecanemab’s Plaque-Clearing Action
- Clinical Evidence for Amyloid Plaque Removal with Lecanemab
- Understanding ARIA: Side Effects of Amyloid-Clearing Therapy
- Who Is Eligible for Lecanemab Treatment and How Amyloid Removal Benefits Them
- The Future of Amyloid-Targeting Therapies Beyond Lecanemab
- How to Prepare
- How to Apply This
- Expert Tips
- Conclusion
- Frequently Asked Questions
What Exactly Are Amyloid Plaques and Why Does Lecanemab Target Them?
amyloid plaques are abnormal clumps of protein that accumulate between nerve cells in the brain, primarily composed of a protein fragment called amyloid-beta (also written as Aβ or A-beta). In a healthy brain, these protein fragments are produced, broken down, and cleared away as part of normal cellular metabolism. In Alzheimer’s disease, this clearance process becomes impaired, allowing amyloid-beta to accumulate. The fragments stick together, first forming small clusters called oligomers, then larger assemblies called protofibrils, and eventually hardening into the dense, insoluble plaques visible on brain imaging and autopsy.
The amyloid hypothesis””the theory that these protein deposits are a primary driver of Alzheimer’s disease””has dominated research for over three decades. According to this framework, amyloid accumulation triggers a cascade of downstream effects: neuroinflammation, tau protein tangles, synaptic dysfunction, and ultimately neuronal death. While debate continues about whether amyloid is the cause or a consequence of the disease, removing these plaques has long been viewed as a potential therapeutic strategy. Lecanemab specifically targets amyloid because of where it acts in this aggregation process. Unlike earlier failed antibody treatments that primarily bound to established plaques, lecanemab preferentially binds to soluble protofibrils””the intermediate-sized aggregates that many researchers consider the most toxic form of amyloid-beta.
- **Protofibrils are highly neurotoxic**: These soluble aggregates can move freely through brain tissue, damaging synapses and disrupting neuronal communication more readily than immobile plaques
- **Targeting protofibrils catches amyloid earlier**: By neutralizing these precursor structures, lecanemab prevents additional plaque formation while also clearing existing deposits
- **The antibody-amyloid complex is cleared by microglia**: Once lecanemab binds to amyloid, the brain’s immune cells recognize and engulf the tagged protein for degradation
The Molecular Mechanism Behind Lecanemab’s Plaque-Clearing Action
Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody, meaning it was originally derived from mouse antibodies but engineered to be compatible with the human immune system. The antibody was designed through a collaboration between Eisai and BioArctic, using a proprietary technology that selected for antibodies with high affinity for amyloid-beta protofibrils. This selectivity is central to understanding how the drug achieves its effects. When lecanemab is administered intravenously, it crosses the blood-brain barrier and enters the central nervous system. The antibody’s binding region (called the Fab fragment) recognizes a specific three-dimensional shape found on amyloid-beta protofibrils and, to a lesser extent, on oligomers and fibrils.
The binding affinity for protofibrils is approximately 1,000 times greater than for monomers (individual amyloid-beta molecules), ensuring the drug targets pathological aggregates rather than normal protein fragments. Once bound, the antibody-amyloid complex is recognized by microglial cells, the brain’s resident immune cells. The Fc region of the antibody (the “tail” portion) binds to Fc receptors on the microglial surface, triggering a process called antibody-dependent cellular phagocytosis. The microglia essentially consume the tagged amyloid, breaking it down within intracellular compartments called lysosomes. This clearance mechanism is highly efficient””clinical trials demonstrated that lecanemab reduced amyloid plaque burden by an average of 59% to 74% over 18 months, as measured by PET imaging.
- **Blood-brain barrier penetration**: Approximately 0.1% of the administered antibody reaches the brain, which sounds small but represents a therapeutically meaningful concentration
- **Half-life considerations**: Lecanemab has a serum half-life of approximately 5-7 days, necessitating infusions every two weeks to maintain effective brain concentrations
- **Dose-dependent clearance**: Higher doses correlate with greater amyloid reduction, though they also increase the risk of side effects
Clinical Evidence for Amyloid Plaque Removal with Lecanemab
The pivotal evidence for lecanemab’s plaque-clearing ability and clinical benefit came from the Clarity AD trial, a global Phase 3 study involving 1,795 participants with early symptomatic Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s). Participants were randomly assigned to receive either lecanemab or placebo infusions every two weeks for 18 months, with the primary outcome being change in a composite cognitive and functional measure called the Clinical Dementia Rating-Sum of Boxes (CDR-SB). The results, published in the New England Journal of Medicine in January 2023, showed that lecanemab reduced clinical decline by 27% compared to placebo””a statistically significant but clinically modest effect that translated to approximately 0.45 points on the 18-point CDR-SB scale. More striking were the amyloid reduction findings: participants receiving lecanemab showed dramatic decreases in brain amyloid levels, while the placebo group showed continued accumulation.
By 18 months, the treatment group had amyloid levels below the threshold typically used to define Alzheimer’s pathology. Secondary analyses revealed that the clinical benefit was correlated with the degree of amyloid clearance. Participants who achieved greater plaque reduction tended to show slower cognitive decline. The treatment effect was also more pronounced on some measures than others””activities of daily living and global cognition showed improvements, while effects on specific memory tests were less consistent.
- **Amyloid PET findings**: Mean reduction of 59 centiloids at 18 months, compared to an increase of 4 centiloids in the placebo group
- **Biomarker changes**: Reductions in plasma p-tau181 and other blood-based Alzheimer’s markers suggested downstream effects on tau pathology
- **Subgroup analyses**: Benefits appeared consistent across age groups, disease stages, and APOE ε4 carrier status, though carriers experienced more side effects
Understanding ARIA: Side Effects of Amyloid-Clearing Therapy
Amyloid-related imaging abnormalities, or ARIA, represent the most significant safety concern with lecanemab and other amyloid-clearing antibodies. ARIA encompasses two related phenomena: ARIA-E (edema or fluid accumulation in the brain) and ARIA-H (microhemorrhages or superficial siderosis). These side effects occur because the rapid clearance of amyloid from blood vessel walls can temporarily compromise vascular integrity, allowing fluid or blood to leak into surrounding brain tissue. In the Clarity AD trial, ARIA-E occurred in 12.6% of lecanemab-treated participants compared to 1.7% receiving placebo. ARIA-H (microhemorrhages) occurred in 17.3% of the treatment group versus 9.0% with placebo. Most ARIA cases were asymptomatic and detected only through routine MRI monitoring required by the protocol.
When symptoms did occur, they typically included headache, confusion, dizziness, nausea, and visual disturbances. The majority of ARIA events resolved within several months, either spontaneously or with temporary treatment interruption. Certain factors significantly increase ARIA risk. Carriers of the APOE ε4 gene variant, which is associated with increased Alzheimer’s risk, experienced ARIA-E at nearly three times the rate of non-carriers (32.6% for homozygotes). Concurrent use of anticoagulants also elevates risk, as does the presence of existing cerebral microhemorrhages. Three deaths in the trial were potentially related to ARIA, though the exact contribution of the drug versus underlying disease remains debated.
- **Mandatory MRI monitoring**: Treatment protocols require baseline MRI and periodic scans throughout treatment to detect ARIA early
- **APOE genotyping considerations**: Genetic testing is recommended before starting treatment so patients can make informed decisions about risk
- **Anticoagulant precautions**: The FDA label warns about increased bleeding risk in patients taking blood thinners
Who Is Eligible for Lecanemab Treatment and How Amyloid Removal Benefits Them
Lecanemab is approved for the treatment of Alzheimer’s disease, but the label specifies that treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease””the same population studied in clinical trials. This limitation exists because no data demonstrate benefit in moderate or advanced Alzheimer’s, and the risk-benefit calculation becomes less favorable as disease progresses. The rationale is straightforward: removing amyloid plaques can only slow decline if there is still enough healthy brain tissue to preserve. Before starting treatment, patients must undergo confirmatory testing to establish the presence of amyloid pathology.
This can be accomplished through amyloid PET imaging or cerebrospinal fluid analysis showing reduced amyloid-beta-42 and elevated phosphorylated tau. Medicare covers lecanemab only when patients are enrolled in registries that collect real-world data, a requirement reflecting lingering questions about the magnitude of clinical benefit outside controlled trial settings. The ideal candidate for lecanemab is someone recently diagnosed with mild cognitive impairment or early Alzheimer’s dementia who has confirmed amyloid pathology, no contraindications to MRI, manageable vascular risk factors, and access to the specialized infusion and monitoring infrastructure required for treatment. Patients on anticoagulant therapy, those with a history of multiple strokes, or individuals with more than four existing microhemorrhages may not be appropriate candidates.
- **Cognitive criteria**: MMSE scores typically between 22-30, indicating preserved baseline function
- **Functional independence**: Patients should still be performing most activities of daily living independently
- **Caregiver involvement**: A reliable care partner is essential for monitoring and reporting potential ARIA symptoms
The Future of Amyloid-Targeting Therapies Beyond Lecanemab
Lecanemab’s approval has catalyzed intense activity in the Alzheimer’s drug development landscape. Donanemab, a similar antibody developed by Eli Lilly that targets a modified form of amyloid-beta, received FDA approval in 2024 after demonstrating 35% slowing of clinical decline in its Phase 3 trial. Unlike lecanemab’s ongoing maintenance therapy, donanemab is administered until amyloid plaques are substantially cleared, then discontinued””a protocol that could reduce treatment burden and cost.
Researchers are also investigating whether combination therapies targeting both amyloid and tau might produce greater clinical benefit than amyloid removal alone. Several anti-tau antibodies are in clinical development, and early-stage trials are exploring whether adding these agents to amyloid-clearing treatment could address the disease more comprehensively. The emergence of highly accurate blood tests for Alzheimer’s pathology may also transform the field, enabling earlier diagnosis and treatment initiation before significant neurodegeneration occurs.
How to Prepare
- **Obtain a formal Alzheimer’s diagnosis**: Before lecanemab can be prescribed, you need a clinical evaluation confirming mild cognitive impairment or mild dementia due to Alzheimer’s disease. This typically involves cognitive testing, medical history review, and ruling out other causes of memory problems such as depression, thyroid dysfunction, or vitamin deficiencies.
- **Confirm amyloid pathology through biomarker testing**: An amyloid PET scan or lumbar puncture for cerebrospinal fluid analysis is required to document the presence of amyloid plaques. Insurance coverage for these tests has improved but remains variable, so verify benefits before scheduling.
- **Complete baseline MRI and safety evaluations**: A brain MRI is mandatory before starting treatment to identify any pre-existing ARIA-like abnormalities, significant vascular disease, or other contraindications. Blood tests, cardiac evaluation, and medication review are also standard.
- **Discuss APOE genetic testing**: While not strictly required, knowing your APOE ε4 status helps inform risk-benefit discussions. Homozygous carriers (two copies of ε4) face substantially higher ARIA risk and should weigh this carefully against potential benefits.
- **Establish care logistics and support systems**: Lecanemab infusions take approximately one hour and occur every two weeks, indefinitely. Identify a reliable infusion center, arrange transportation, and ensure a care partner can accompany you to appointments and monitor for side effects at home.
How to Apply This
- **Locate a certified treatment center**: Not all neurology practices offer lecanemab infusions. Academic medical centers, larger neurology groups, and some community infusion centers have established programs. Your diagnosing neurologist can provide referrals.
- **Navigate insurance authorization and registry enrollment**: Medicare requires enrollment in a qualified data registry before covering treatment. Private insurers have varying requirements. Work with the treatment center’s financial counselors to understand costs, which can exceed $26,000 annually before insurance.
- **Adhere to the monitoring schedule**: Expect MRIs before infusions 5, 7, and 14, with additional scans if ARIA is suspected. Blood pressure monitoring and symptom assessment occur at each visit. Do not skip monitoring appointments, as early ARIA detection prevents serious complications.
- **Communicate promptly about new symptoms**: Headache, confusion, dizziness, vision changes, or nausea developing after infusion should be reported immediately to your treatment team. These may indicate ARIA requiring evaluation and possible treatment hold.
Expert Tips
- **Start a symptom diary before treatment begins**: Documenting baseline cognitive fluctuations, headaches, and other symptoms helps distinguish normal variability from potential treatment-related changes later.
- **Coordinate with all prescribing physicians about anticoagulants**: If you take blood thinners for heart conditions, your cardiologist and neurologist must communicate about risk management. Some patients may need to switch medications or accept modified treatment protocols.
- **Plan for the psychological impact of treatment**: The commitment to indefinite biweekly infusions, repeated MRIs, and constant monitoring is substantial. Patients who accept this as their new normal from the outset often cope better than those who view it as temporary inconvenience.
- **Engage family members in monitoring**: Cognitive symptoms of ARIA may not be apparent to the patient. Family members who observe changes in thinking, behavior, or coordination should have direct contact information for the treatment team.
- **Maintain realistic expectations**: Lecanemab slows decline but does not restore lost function or stop progression entirely. Understanding that success means slower worsening rather than improvement helps prevent disappointment and treatment abandonment.
Conclusion
The approval of lecanemab represents a genuine advance in Alzheimer’s disease treatment, offering the first therapy proven to both remove amyloid plaques and slow clinical decline in early symptomatic disease. The mechanism is elegant in concept””using engineered antibodies to tag toxic protein aggregates for clearance by the brain’s own immune cells””though the implementation involves substantial complexity in patient selection, administration, and monitoring. For appropriate candidates, the therapy provides a meaningful opportunity to preserve cognitive function longer than would otherwise be possible. The path forward involves both individual decisions and systemic changes.
Patients and families must weigh modest clinical benefits against real risks and significant logistical demands. Healthcare systems must expand access to specialized diagnosis, infusion infrastructure, and long-term monitoring. Researchers continue working toward more effective treatments, earlier intervention, and ultimately prevention. While lecanemab is not a cure, it represents proof that modifying Alzheimer’s disease biology is achievable””a foundation upon which better therapies will be built.
Frequently Asked Questions
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Results vary depending on individual circumstances, but most people begin to see meaningful progress within 4-8 weeks of consistent effort. Patience and persistence are key factors in achieving lasting outcomes.
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