Recent breakthroughs have revealed exactly how two FDA-approved Alzheimer’s drugs work at the cellular level—and the findings reshape our understanding of how to slow cognitive decline. Lecanemab (Leqembi) and donanemab (Kisunla) achieve their effects through carefully targeted mechanisms that activate the brain’s own immune cells to remove amyloid buildup, though they work in distinctly different ways.
For lecanemab, 2025 research published in Nature Neuroscience shows it specifically targets amyloid protofibrils and triggers microglia—the brain’s resident immune cells—to engulf and break down plaques through enhanced phagocytosis and metabolic reprogramming. Donanemab takes a different route, honing in on truncated amyloid forms that accumulate in plaques and achieving faster clearance while also reducing phosphorylated tau, a second hallmark protein of Alzheimer’s disease. This article explores how each mechanism works, what makes them different, and the emerging non-amyloid approaches scientists are now investigating to tackle Alzheimer’s from entirely new angles.
Table of Contents
- How Do Leading Alzheimer’s Drugs Target Amyloid Plaques?
- Lecanemab and Microglial-Mediated Clearance: Understanding the Process
- Donanemab’s Distinct Approach and Tau Biomarker Reduction
- Choosing the Right Treatment: Comparing Available Options
- Limitations and Challenges in Current Amyloid-Targeting Therapies
- Emerging Non-Amyloid Approaches: Epigenetic and Glymphatic Innovations
- The Future of Alzheimer’s Treatment: Multiple Mechanisms in Development
- Conclusion
How Do Leading Alzheimer’s Drugs Target Amyloid Plaques?
The two FDA-approved monoclonal antibodies approved for early Alzheimer’s disease work by binding to different forms of amyloid-beta, the protein fragment that clumps into plaques in the Alzheimer’s brain. Lecanemab was the first to receive approval, and its mechanism centers on recognizing amyloid protofibrils—the small, toxic clusters that form before full-sized plaques develop. Once lecanemab binds to these protofibrils, it flags them for destruction by microglia, which then engulf the tagged proteins. The actual clearance involves several steps: microglia increase their phagocytic capacity, activate lysosomal degradation pathways to break down what they’ve ingested, and undergo metabolic reprogramming that keeps them in a pro-clearance state. Recent 2025 research reveals lecanemab also activates interferon gamma genes and antigen presentation pathways, essentially enlisting the brain’s immune system more broadly to participate in cleanup.
Donanemab, approved more recently, targets an even more specific amyloid form: N-terminally truncated amyloid-beta that predominates in actual plaques. This specificity matters because it allows faster amyloid clearance compared to lecanemab, particularly in people with intermediate tau burden. While lecanemab focuses on preventing plaque formation by targeting protofibrils, donanemab’s approach is more aggressive at dismantling existing plaques. Both drugs achieve measurable reductions in blood biomarkers of neurodegeneration, including phosphorylated tau-181, neurofilament light chain, and glial fibrillary acidic protein (GFAP)—proteins that leak into the bloodstream when neurons and glial cells are damaged. However, the differences in their target specificity mean patient response can vary, making the choice of which drug to use partly dependent on someone’s individual amyloid and tau status.
Lecanemab and Microglial-Mediated Clearance: Understanding the Process
Lecanemab’s mechanism reveals something fundamental: you don’t need to physically extract amyloid from the brain—you just need to convince the brain’s own cleanup crew to do it more efficiently. Microglia naturally patrol the brain and engulf cellular debris, but in Alzheimer’s disease, they become dysfunctional and fail to clear amyloid effectively. Lecanemab restores this function by opsonizing amyloid protofibrils, a term borrowed from immunology meaning to “mark for destruction.” The antibody coating makes protofibrils visible and appetizing to microglia, which then increase their uptake and degradation. The 2025 Nature Neuroscience data showing activation of interferon gamma pathways suggests lecanemab also shifts microglia into a more pro-inflammatory, tissue-protective state rather than allowing them to remain in a chronically activated, damaging configuration that characterizes neuroinflammation in Alzheimer’s. This mechanism does have a significant limitation: it requires lecanemab to reach the amyloid before it becomes fully embedded in dense plaques.
Early-stage amyloid pathology—the protofibril-rich phase—is when lecanemab works most effectively. If too much plaque has already mineralized and cross-linked, the antibody may have difficulty accessing those deposits. This is partly why lecanemab is approved only for people with mild cognitive impairment or mild dementia stage and confirmed amyloid pathology, not for moderate or advanced Alzheimer’s. The drug also carries a risk of amyloid-related imaging abnormalities (ARIA)—brain swelling or microhemorrhages that occur as amyloid is rapidly cleared. These side effects affect roughly 10–20% of people taking the drug and necessitate regular MRI monitoring, a practical constraint that limits who can receive lecanemab safely.
Donanemab’s Distinct Approach and Tau Biomarker Reduction
Donanemab offers a mechanistically distinct advantage: by targeting truncated amyloid fragments that predominate in mature plaques, it can achieve clearance of more established amyloid pathology than lecanemab alone. The molecule was engineered to bind N-terminal variants of amyloid that accumulate in the plaques of people who are further along in the disease process. Clinical trial data shows donanemab produces more rapid amyloid PET decline on imaging and more consistent reductions in plasma phosphorylated tau-181, a marker that predicts cognitive decline. The fact that it also lowers GFAP and neurofilament light chain—markers of glial activation and neuronal damage—suggests the drug may be slowing the cascade of secondary neurodegeneration that follows amyloid accumulation. What distinguishes donanemab further is its dosing regimen.
It requires fewer infusions than lecanemab, which appeals to patients and healthcare systems alike, though both drugs require intravenous administration and medical supervision. The comparative data from trials shows donanemab achieving amyloid clearance in intermediate-tau populations somewhat more efficiently than lecanemab, though differences in patient populations and trial designs make direct head-to-head comparison complex. However, donanemab also carries ARIA risk and requires MRI monitoring. Neither drug eliminates amyloid completely or restores cognitive function that’s already been lost; both are designed to slow decline in early symptomatic stages, and absolute cognitive benefits remain modest—roughly 25–35% slowing of decline over 18 months in clinical trials. For many patients, this translates to postponing progression to the next stage of dementia by several months, a meaningful but limited intervention.
Choosing the Right Treatment: Comparing Available Options
For clinicians and patients considering amyloid-targeting therapy, the choice between lecanemab and donanemab hinges on several practical factors. Lecanemab has longer real-world data from earlier trials and commercial use since its 2023 approval, making it a known quantity with well-characterized side effect patterns. Donanemab is newer, requires fewer infusions (initially six infusions over eight weeks versus lecanemab’s twice-weekly infusions), and shows slightly faster amyloid clearance. If someone has primarily protofibril-rich amyloid pathology (detected on amyloid PET imaging), lecanemab might be more targeted. If someone is further along with established plaques and truncated amyloid forms, donanemab’s specificity may be advantageous.
In practice, though, most centers lack sophisticated amyloid PET imaging, so the choice often comes down to physician experience, insurance coverage, and logistical feasibility of the infusion schedule. A critical practical consideration is that neither drug works alone in advanced disease. Both are approved only for mild cognitive impairment or mild dementia with confirmed amyloid positivity—if someone already has moderate or severe cognitive decline, these therapies have not been studied and are not indicated. This means the window for treatment is narrow, and early detection through cognitive screening and biomarker testing becomes essential. Some patients and families hope to start treatment before any cognitive symptoms appear, based on amyloid and tau biomarkers alone, but current approvals don’t yet extend to that asymptomatic stage, though trials are underway. The monthly cost of both drugs runs $25,000–$30,000 before insurance, making access disparate based on geography, insurance status, and ability to navigate infusion centers.
Limitations and Challenges in Current Amyloid-Targeting Therapies
Despite the mechanism-of-action breakthroughs, amyloid-targeting drugs face a hard truth: not everyone responds equally, and amyloid removal alone may not be sufficient for advanced disease stages. Some people with confirmed amyloid pathology show minimal cognitive decline over years, while others progress rapidly—suggesting amyloid is necessary but not sufficient for Alzheimer’s pathology. Tau tangles, another hallmark protein, appear to matter more for actual neuronal death and cognitive decline once they’re abundant. Lecanemab and donanemab reduce phosphorylated tau in blood, indicating they may slow tau-related damage, but whether they directly clear tau from the brain remains unclear. For people who have already developed moderate dementia with both abundant amyloid and widespread tau tangles, the clinical evidence suggests these drugs offer little benefit—the brain damage has progressed beyond what amyloid removal alone can address.
The infrastructure required for safe amyloid-targeting therapy also represents a hidden limitation. Both drugs require regular MRI scans to monitor for ARIA, access to infusion centers, neurological evaluation, and baseline cognitive testing. In rural areas or low-income regions, this infrastructure doesn’t exist, creating a two-tiered system where access to cutting-edge Alzheimer’s treatment depends on geography and resources. Additionally, the need for intravenous administration means people with poor venous access, those on anticoagulants with bleeding concerns, or those who are medically frail may not be eligible. The anti-amyloid monoclonal antibody approach, while biologically elegant, is therefore practically complex and suitable for a narrow, early-disease, well-resourced population rather than the broader Alzheimer’s population.
Emerging Non-Amyloid Approaches: Epigenetic and Glymphatic Innovations
While lecanemab and donanemab target amyloid, researchers are pursuing entirely different disease mechanisms. One striking approach revealed in March 2026 involves an experimental drug called FLAV-27 that reverses memory loss through epigenetic mechanisms rather than amyloid removal. The drug inhibits the G9a enzyme, which is responsible for certain histone methylation patterns in neurons. In Alzheimer’s disease, G9a activity becomes dysregulated, silencing genes needed for neuronal communication and plasticity. By blocking G9a, FLAV-27 restores normal gene expression patterns and reverses memory deficits in preclinical models. This mechanism is distinct not only from amyloid removal but suggests Alzheimer’s disease might be partly understood as an epigenetic disorder—one where normal gene regulation breaks down rather than just protein accumulation killing neurons.
Another emerging approach targets the glymphatic system, the brain’s waste-clearance highway that removes toxins during sleep. Recent data shows a drug combination called ACX-02 enhances slow brain waves during sleep, which in turn increases the flow of cerebrospinal fluid through the brain and enhances clearance of amyloid and tau along glymphatic channels. Rather than directly attacking amyloid, this approach optimizes the brain’s natural housekeeping function. A February 2026 finding from Indiana University reveals that removing the IDOL enzyme from neurons substantially reduces amyloid plaques while improving neuronal communication and metabolism. These mechanisms highlight a critical insight: amyloid accumulation may be as much a symptom of failed clearance and metabolic dysfunction as it is a primary cause of neurodegeneration. Targeting these upstream processes could potentially prevent amyloid accumulation rather than remove it after the fact.
The Future of Alzheimer’s Treatment: Multiple Mechanisms in Development
The convergence of lecanemab and donanemab approvals alongside emerging epigenetic, glymphatic, and metabolic approaches suggests the future of Alzheimer’s treatment will likely involve combination therapy—striking the disease from multiple angles simultaneously. Just as cancer treatment evolved from single-drug chemotherapy to multi-agent regimens targeting different pathways, Alzheimer’s treatment appears headed toward combining amyloid-targeting antibodies with drugs that restore epigenetic regulation, optimize glymphatic clearance, and stabilize neuronal metabolism. The fact that these mechanisms are mechanistically distinct means blocking one pathway shouldn’t render another ineffective, opening the possibility of additive or synergistic benefit. Clinical trials exploring these combinations are now underway, though results won’t be available for several years.
A broader lesson from recent mechanism-of-action discoveries is that Alzheimer’s disease is not a single-protein disease but a cascade of interconnected failures: protein misfolding, impaired clearance, epigenetic dysregulation, neuroinflammation, and metabolic dysfunction all feed each other. Early intervention—before extensive neuronal death occurs—appears essential, which is why the field is shifting toward detecting amyloid and tau biomarkers in asymptomatic people. This strategy will require widespread plasma biomarker screening to identify people at risk, a transformation in how we approach brain health as preventive rather than just curative. The mechanisms now being revealed by lecanemab and donanemab represent major steps forward, but they are the beginning of a much longer process of understanding and treating the disease.
Conclusion
The mechanisms of action for lecanemab and donanemab have finally moved Alzheimer’s treatment from symptomatic relief to disease-modifying intervention, even if modestly. Lecanemab’s activation of microglial-mediated amyloid clearance and donanemab’s targeting of truncated plaque amyloid represent two distinct but complementary approaches to removing amyloid burden in early disease. Both drugs demonstrate that antibody-based amyloid removal can slow cognitive decline and reduce neurodegeneration biomarkers, though the clinical benefit remains approximately 25–35% slowing of decline and access remains limited by infrastructure, cost, and the narrow window of early disease in which they’re approved. Yet the most exciting insight from recent research is that amyloid removal is only one of several mechanisms through which we can intervene in Alzheimer’s disease.
Epigenetic restoration, glymphatic system optimization, metabolic repair, and inflammatory modulation offer alternative or complementary pathways. The future likely involves combination therapies targeting multiple mechanisms before cognitive decline becomes severe. For now, if you or a family member has mild cognitive impairment or mild dementia with confirmed amyloid pathology, discussing lecanemab or donanemab with a neurologist is warranted—these are the first disease-modifying drugs with proven benefit. At the same time, maintaining cognitive engagement, cardiovascular health, sleep quality, and social connection remains important for brain health regardless of drug status, as these factors influence the underlying metabolic and neuroinflammatory processes that these emerging mechanisms are designed to address.
