Donanemab – A New Chapter in the Treatment of Alzheimer’s Disease
What You Need to Know About the Therapies That Aim to Slow Disease Progression
Until just a few years ago, receiving a diagnosis of Alzheimer’s disease was almost always followed by the same conversation: while several medications could temporarily alleviate certain symptoms, none could alter the course of the disease itself. Despite decades of intensive research, hundreds of clinical trials had failed, and many scientists had begun to question whether the underlying theory guiding Alzheimer’s research was even correct.
Today, that landscape is beginning to change.
The emergence of anti-amyloid monoclonal antibodies, such as lecanemab and, more recently, donanemab, represents one of the most significant breakthroughs in modern neurology. These drugs do not cure Alzheimer’s disease, nor do they restore lost memories. However, they are the first therapies to demonstrate in large clinical trials that they can slow the progression of the disease in carefully selected patients.
This distinction is crucial.
For the first time, medicine is no longer focusing solely on treating the consequences of Alzheimer’s disease—it is attempting to intervene in one of the biological mechanisms believed to drive it.
In this article, we will explore what donanemab is, how it works, why it differs from traditional Alzheimer’s medications, and what both its benefits and limitations are.
Why Is Alzheimer’s Disease So Difficult to Treat?
Alzheimer’s disease is the most common cause of dementia, accounting for approximately 60–70% of all dementia cases worldwide. Tens of millions of people are currently living with the disease, and as life expectancy continues to increase, this number is expected to rise dramatically over the coming decades.
For many years, memory loss was considered an inevitable part of aging. We now know that this is far from true.
The brains of people with Alzheimer’s disease undergo two hallmark pathological changes:
- the accumulation of beta-amyloid plaques outside neurons;
- the formation of neurofibrillary tangles composed of the tau protein inside neurons.
Remarkably, these changes begin 15 to 20 years before the first noticeable symptoms appear.
During this long silent phase, the disease progresses unnoticed. The brain initially compensates for the gradual loss of neurons, allowing cognitive function to remain relatively normal. Symptoms only become apparent after substantial and irreversible neuronal damage has already occurred.
This explains one of the greatest challenges in treating Alzheimer’s disease: by the time the diagnosis is made, many neurons have already been permanently lost.
From Symptom Management to Disease Modification
Until recently, the standard treatment for Alzheimer’s disease consisted of medications such as donepezil, rivastigmine, galantamine, and memantine.
These drugs can temporarily improve memory, attention, or daily functioning in some patients. However, they do not halt the neurodegenerative process.
In other words, patients may experience a period of stabilization, but the disease continues to progress.
This realization led researchers to pursue a far more ambitious goal: developing therapies capable of changing the course of the disease itself.
These medications are known as disease-modifying therapies (DMTs).
Rather than simply reducing symptoms, they aim to interfere with the biological processes responsible for Alzheimer’s disease.
The Amyloid Hypothesis – A Theory That Divided the Scientific Community
Beginning in the 1990s, researchers observed that nearly every patient with Alzheimer’s disease had significant deposits of beta-amyloid in the brain.
This led to the amyloid hypothesis, which proposed that beta-amyloid accumulation is one of the earliest events triggering the cascade of neurodegeneration.
If this hypothesis were correct, removing beta-amyloid should slow the progression of Alzheimer’s disease.
The theory seemed straightforward.
Reality proved far more complicated.
Over the next two decades, numerous experimental drugs designed to eliminate beta-amyloid failed in clinical trials. Some did not remove enough amyloid; others produced unacceptable side effects. Even more frustratingly, some medications successfully reduced amyloid plaques without providing meaningful clinical improvement.
These repeated failures led many experts to question whether the amyloid hypothesis was fundamentally flawed.
Today, our understanding is more nuanced.
Most scientists believe that beta-amyloid represents only one piece of a highly complex disease process involving tau pathology, chronic neuroinflammation, immune system dysfunction, vascular changes, and genetic susceptibility.
Nevertheless, growing evidence suggests that reducing amyloid burden can slow disease progression—provided treatment begins early enough, before extensive neuronal loss has occurred.
The First Anti-Amyloid Antibodies
The first monoclonal antibody to capture worldwide attention was aducanumab.
Its approval generated enormous controversy.
Although aducanumab effectively removed beta-amyloid plaques from the brain, many experts argued that the available evidence did not convincingly demonstrate a meaningful clinical benefit.
The debate became so intense that several regulatory agencies declined to approve the drug, while its use remained extremely limited in many countries.
Despite the controversy, aducanumab accomplished something important.
It proved that removing amyloid plaques from the human brain was biologically possible.
This paved the way for a new generation of therapies.
Two monoclonal antibodies subsequently provided much stronger clinical evidence:
- Lecanemab, which primarily targets soluble beta-amyloid protofibrils believed to be particularly toxic to neurons.
- Donanemab, which recognizes a modified form of beta-amyloid found predominantly within mature amyloid plaques.
Together, these therapies have fundamentally changed the direction of Alzheimer’s research and opened the door to a new era of disease-modifying treatments.
What Is Donanemab?
Donanemab is a humanized IgG1 monoclonal antibody specifically engineered to recognize a unique target within the brain.
Rather than binding to all forms of beta-amyloid, it selectively targets N3pG beta-amyloid, a modified version of the protein found primarily in mature amyloid plaques characteristic of Alzheimer’s disease.
Once attached to these plaques, donanemab activates microglia, the brain’s resident immune cells.
These cells then begin clearing the amyloid deposits from the brain.
Importantly, the goal of donanemab is not to regenerate neurons that have already died.
Unfortunately, modern medicine cannot yet accomplish that.
Instead, the objective is to reduce the brain’s amyloid burden early enough to slow the neurodegenerative process before irreversible neuronal damage becomes too extensive.
This is the fundamental difference between donanemab and traditional Alzheimer’s medications.
Rather than simply masking symptoms, it attempts to intervene directly in one of the biological mechanisms believed to contribute to the disease itself.
Donanemab vs. Lecanemab – Two Drugs from the Same Family, but Not the Same
Both lecanemab and donanemab belong to the same therapeutic class: anti-amyloid monoclonal antibodies. Their primary goal is to reduce the accumulation of beta-amyloid in the brain and slow the progression of Alzheimer’s disease during its earliest stages.
Despite sharing the same overall objective, these medications differ in several important ways.
Lecanemab primarily targets soluble beta-amyloid protofibrils, toxic aggregates believed to play a crucial role in the early stages of Alzheimer’s disease. Donanemab, on the other hand, specifically recognizes a modified form of beta-amyloid known as N3pG beta-amyloid, which is predominantly found in mature amyloid plaques.
Although this distinction may seem highly technical, it helps explain why the two therapies follow different treatment strategies.
Lecanemab is administered as an intravenous infusion every two weeks and is generally intended as continuous therapy. Donanemab is administered once monthly, and in selected patients treatment may be discontinued after imaging studies demonstrate that most amyloid plaques have been removed. This „treat-to-target” strategy is one of the most distinctive features of donanemab.
It is important to emphasize, however, that stopping treatment does not mean the patient has been cured. Alzheimer’s disease continues to progress, and ongoing clinical follow-up remains essential.
How Is Donanemab Administered?
Unlike most neurological medications, donanemab is not a pill that patients take at home.
It is administered as an intravenous infusion in a specialized healthcare facility under medical supervision.
Before treatment can begin, several important steps are required:
- confirmation of the diagnosis of Alzheimer’s disease;
- evidence of brain amyloid pathology, typically obtained through amyloid PET imaging or cerebrospinal fluid biomarkers;
- a baseline brain MRI;
- assessment of the patient’s individual risk factors for treatment-related adverse events.
Throughout therapy, additional MRI scans are performed at regular intervals to detect potential brain abnormalities before they become clinically significant.
Consequently, donanemab is not a treatment that can simply be prescribed and forgotten. It requires a multidisciplinary team that may include neurologists, neuroradiologists, specialized nursing staff, and imaging experts capable of monitoring patients throughout the course of therapy.
What Have Clinical Trials Shown?
The most important question is, naturally:
Does it work?
The answer is yes—but with important limitations.
The pivotal clinical trial evaluating donanemab was TRAILBLAZER-ALZ 2, which enrolled more than 1,700 patients with either mild cognitive impairment (MCI) due to Alzheimer’s disease or mild Alzheimer’s dementia, all with confirmed amyloid pathology.
Participants were followed for approximately 18 months.
The study demonstrated that patients receiving donanemab experienced slower cognitive and functional decline compared with those receiving placebo.
This finding deserves careful interpretation.
The drug did not improve memory or restore cognitive abilities that had already been lost.
Instead, it slowed the rate at which the disease progressed.
Although this distinction may appear subtle, it can have enormous practical significance.
For patients and their families, slowing disease progression may translate into additional months—or even years—during which independence is better preserved, daily activities remain manageable, and admission to long-term care facilities can potentially be delayed.
Why Must These Results Be Interpreted Carefully?
In recent years, many media headlines have suggested that researchers have finally „found a cure for Alzheimer’s disease.”
Such statements are misleading.
Donanemab does not stop Alzheimer’s disease.
It does not regenerate damaged neurons.
It does not reverse dementia.
Its benefit is incremental rather than transformative.
In clinical trials, both the treatment group and the placebo group continued to decline over time.
The difference was that decline occurred more slowly among patients receiving donanemab.
This is an essential point that every patient and family should understand before considering treatment.
We are not talking about a miracle cure.
We are witnessing the first meaningful step toward therapies capable of altering the biological course of a disease that, until recently, was considered essentially untreatable.
The Earlier the Treatment Begins, the Greater the Potential Benefit
One of the most important lessons learned from recent Alzheimer’s research is that timing matters enormously.
Alzheimer’s disease begins many years before symptoms become clinically apparent.
By the time patients develop moderate or severe dementia, millions of neurons have already been irreversibly lost.
Removing amyloid plaques at that stage cannot bring those neurons back.
This explains why donanemab is intended for individuals in the earliest symptomatic phases of Alzheimer’s disease.
This represents a profound shift in the way neurologists think about Alzheimer’s.
In the past, making an early diagnosis had relatively limited therapeutic implications because no disease-modifying treatments were available.
Today, early diagnosis has become critically important.
Over the coming years, neurologists are likely to place increasing emphasis on biomarkers, advanced neuroimaging, and biological confirmation of Alzheimer’s pathology so that treatment can begin before irreversible neuronal damage becomes extensive.
Who Is Eligible for Donanemab?
Not every person experiencing memory problems is a candidate for this therapy.
Current clinical evidence supports the use of donanemab primarily in patients with:
- mild cognitive impairment (MCI) due to Alzheimer’s disease;
- mild Alzheimer’s dementia;
- confirmed evidence of brain amyloid pathology;
- appropriate MRI findings and overall clinical eligibility.
In practice, this means that memory loss alone is not sufficient to justify treatment.
Many other conditions—including depression, vitamin B12 deficiency, hypothyroidism, medication side effects, sleep disorders, and other forms of dementia—can produce symptoms that resemble Alzheimer’s disease.
Therefore, establishing the diagnosis with the highest possible degree of certainty is essential before initiating anti-amyloid therapy.
Precision Medicine Is Beginning to Transform Neurology
One of the most fascinating aspects of these new therapies is that Alzheimer’s disease management is starting to resemble modern oncology and immunology.
A clinical diagnosis alone is no longer enough.
Physicians increasingly rely on biomarkers, genetic information, advanced neuroimaging, and an individual’s risk profile to determine whether treatment is appropriate.
This approach is known as precision medicine.
In the future, Alzheimer’s disease is unlikely to be treated with a single medication prescribed to everyone.
Instead, therapy will probably become increasingly personalized, combining multiple drugs selected according to each patient’s unique biological profile.
Are There Risks? Absolutely — and They Should Not Be Overlooked
Whenever a new treatment emerges, public attention naturally focuses on its potential benefits. In the case of donanemab, however, discussing its risks is just as important as highlighting its promise.
The best-known adverse effect associated with anti-amyloid therapies is a phenomenon called ARIA (Amyloid-Related Imaging Abnormalities). These changes are detected on brain MRI scans and represent one of the greatest challenges associated with this new class of medications.
ARIA is not a single condition but rather an umbrella term that includes two main types of abnormalities:
- ARIA-E, characterized by temporary swelling of the brain (vasogenic edema) or localized fluid accumulation.
- ARIA-H, which refers to cerebral microhemorrhages or superficial siderosis caused by tiny amounts of bleeding within the brain.
In many patients, these findings produce no symptoms at all and are discovered only during routine MRI monitoring. However, some individuals may experience headaches, dizziness, nausea, confusion, visual disturbances, or, more rarely, seizures.
Fortunately, most cases of ARIA are mild and resolve either spontaneously or after temporarily interrupting treatment. Nevertheless, severe complications—including rare fatal cases—have been reported, underscoring why careful patient selection and regular MRI surveillance are mandatory throughout treatment.
Why Does ARIA Occur?
Although the exact mechanism has not yet been fully established, researchers believe that ARIA results from the rapid removal of amyloid deposits from the walls of cerebral blood vessels.
In other words, the treatment works by clearing amyloid—but this rapid clearance may temporarily alter the integrity of fragile blood vessels in susceptible individuals, leading to localized edema or microscopic bleeding.
This explains why anti-amyloid therapy cannot be prescribed without close neurological supervision.
Who Is at Higher Risk?
Clinical studies have identified several factors associated with an increased likelihood of developing ARIA.
These include:
- carrying the APOE ε4 genetic variant, particularly individuals who inherited two copies of the gene;
- evidence of cerebral amyloid angiopathy;
- multiple pre-existing cerebral microhemorrhages detected on MRI;
- in selected cases, the concurrent use of anticoagulant medications.
For this reason, many specialized Alzheimer’s centers perform genetic testing and detailed MRI evaluations before initiating therapy.
Importantly, the presence of one or more risk factors does not automatically exclude a patient from treatment. Instead, physicians must carefully weigh the expected benefits against the potential risks on an individual basis.
Why Can’t Every Patient with Alzheimer’s Disease Receive Donanemab?
A common question is:
If the drug works, why isn’t it prescribed to everyone with Alzheimer’s disease?
The answer lies in one of the fundamental principles of medicine:
Every treatment must provide more benefit than harm.
In patients with advanced Alzheimer’s disease, extensive neuronal damage has already occurred. At that stage, removing amyloid plaques is unlikely to produce substantial clinical improvement because the neurons responsible for memory and cognition have already been lost.
The treatment’s risks, however, remain.
Consequently, anti-amyloid antibodies are intended primarily for patients in the earliest symptomatic stages, when a significant amount of functional brain tissue can still be preserved.
Is Donanemab a Miracle Cure?
The answer is unequivocally no.
Scientific progress should always be accompanied by realistic expectations.
Donanemab does not cure Alzheimer’s disease.
It does not restore lost memories.
It does not regenerate damaged neurons.
It does not prevent patients from eventually developing more advanced dementia.
What it can do is slow the progression of the disease in carefully selected patients.
For families facing Alzheimer’s disease, even several additional months—or years—of greater independence can be profoundly meaningful.
The opportunity for a loved one to remain independent longer, recognize family members, continue meaningful conversations, or participate in everyday life represents a benefit that cannot be fully captured by statistical measurements alone.
What Does the Future Hold for Alzheimer’s Treatment?
If we look back at the history of medicine, an interesting pattern emerges.
The first statins were far less effective than those available today.
The earliest biologic therapies for rheumatoid arthritis have evolved into highly sophisticated treatments.
The first cancer immunotherapies represented only the beginning of an entirely new era.
Alzheimer’s disease is likely following a similar path.
Donanemab and lecanemab are not the end of the story.
They are the beginning of a new chapter.
Researchers are currently investigating numerous additional therapeutic strategies, including:
- monoclonal antibodies targeting tau protein;
- medications designed to reduce neuroinflammation;
- therapies that protect synaptic function;
- drugs aimed at stimulating the brain’s natural repair mechanisms;
- combination therapies that simultaneously target multiple disease pathways, much like modern treatments for cancer or HIV.
Future Alzheimer’s treatment is unlikely to rely on a single medication.
Instead, patients will probably receive individualized therapeutic combinations based on their genetic profile, biomarkers, imaging findings, and disease stage.
One Essential Point That Should Never Be Forgotten
Despite the excitement surrounding these new medications, drug therapy represents only one component of Alzheimer’s care.
Managing cardiovascular risk factors, engaging in regular physical activity, maintaining a healthy diet, participating in cognitive stimulation programs, ensuring adequate sleep, treating depression, and preserving social engagement remain critically important for both reducing the risk of cognitive decline and supporting individuals already living with Alzheimer’s disease.
No medication can replace these fundamental aspects of brain health.
Conclusions
For more than twenty years, Alzheimer’s research was marked by disappointment. Countless promising compounds showed encouraging laboratory results only to fail during clinical trials, leading many experts to question whether disease-modifying therapy would ever become a reality.
The emergence of anti-amyloid monoclonal antibodies has begun to change that perspective.
Donanemab is not a miracle drug, nor does it cure Alzheimer’s disease. However, it is among the first therapies to convincingly demonstrate that the biological course of Alzheimer’s can be modified—albeit modestly and only in carefully selected patients.
Perhaps its greatest significance lies not only in what it accomplishes today, but in what it represents for the future.
Donanemab provides proof that targeting the underlying biology of Alzheimer’s disease is possible, paving the way for increasingly effective, safer, and more personalized treatments.
Only a few years ago, the idea of slowing the progression of Alzheimer’s disease seemed almost unimaginable.
Today, that goal is beginning to become a reality.
It is not the end of the fight against the world’s most common form of dementia—but it is undoubtedly one of the most important milestones in the history of modern neurology.
Selected References
- Sims JR, et al. Donanemab in Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 2). The New England Journal of Medicine. 2023.
- van Dyck CH, et al. Lecanemab in Early Alzheimer’s Disease. The New England Journal of Medicine. 2023.
- Cummings J, et al. Alzheimer’s Disease Drug Development Pipeline. Alzheimer’s & Dementia.
- European Medicines Agency (EMA). Kisunla (Donanemab): European Assessment Report.
- National Institute on Aging (NIA). What Are Monoclonal Antibodies for Alzheimer’s Disease?
