The Food and Drug Administration (FDA) has authorized a few new medications for treating Alzheimer’s disease since 2021, breaking a nearly two-decade hiatus. Targeting harmful protein aggregates in the brain, most of these medications are antibody therapies. Their endorsement has generated equal parts excitement and controversy. In this Special Feature, we look into the fundamental question of whether these medications are actually having an impact.
Alzheimer’s is a neurodegenerative illness that causes thinking, memory, and eventually the capacity to carry out daily tasks to gradually and irreversibly deteriorate. Since an aging population is the primary risk factor for Alzheimer’s disease, it has become a public health emergency. Globally, there were 57 million cases of Alzheimer’s disease in 2019, and by 2050, there are predicted to be 153 million cases. This emphasizes the necessity of developing disease-modifying therapies that alter the course of the illness permanently and slow its advancement.
However, attempts to create Alzheimer’s disease-modifying treatments have not been effective up until recently. The majority of clinical research aimed at creating Alzheimer’s disease-modifying treatments has concentrated on the beta-amyloid protein, whose aberrant build-up is widely thought to be the initial cause of this neurodegenerative condition. When the Food and Drug Administration (FDA) approved aducanumab, an antibody that targets amyloid-beta protein deposits, for the treatment of Alzheimer’s disease in 2021, it was regarded as the first disease-modifying medication for the illness.
However, aducanumab’s manufacturer, Biogen, announced that it would eventually stop selling the drug after the clinical trials did not yield consistent improvements in cognitive function. Since then, phase 3 clinical trials have shown that two additional anti-amyloid antibodies Biogen’s lecanemab and Eli Lily’s donanemab can slow the cognitive decline of people with early Alzheimer’s disease, and they have been approved by the FDA. Clinicians and researchers alike have greeted the approval of lecanemab and donanemab with enthusiasm, seeing it as a breakthrough after decades of clinical research having failed to yield effective disease-modifying therapies.
However, pointing to safety concerns and a lack of cost-effectiveness, some researchers have expressed concerns about the modest clinical benefits conferred by these anti-amyloid therapies. Dag Aarsland, even though there are obstacles in the fields of medicine, society, and clinical research, we must also acknowledge the advancements that have been made possible by the fact that, following years of expensive and fruitless research, we now possess clear proof of the possibility of slowing the advancement of the disease. The introduction of these medications may hasten the development of treatments and revolutionize clinical services for Alzheimer’s disease, the most common cause of dementia globally, according to Paresh Malhotra, PhD, who also noted that despite the anti-amyloid therapies’ modest efficacy, it is important to acknowledge that these drugs are the first to have clinical effects that appear to relate to a key mechanism of disease progression.
Based on the amyloid cascade theory, anti-amyloid antibody treatments like lecanemab and donanemab were developed. This theory states that the buildup of beta-amyloid protein causes additional alterations in the brain, ultimately resulting in the onset of Alzheimer’s disease. In particular, it is thought that the production of beta-amyloid aggregates causes oxidative stress, inflammation, neuronal damage, loss of synapses the “links between neurons that allow them to communicate” and, eventually, cognitive decline. This is supported by the fact that beta-amyloid protein buildup occurs several years before cognitive function, such as memory and decision-making, declines.
After secretase enzymes cleave a larger amyloid precursor protein, the beta-amyloid protein is produced. The units of the beta-amyloid protein are called monomers, and these monomers can combine to form oligomers, which are soluble short chains made up of two to more than fifty monomers. In addition to forming larger, soluble protofibrils and insoluble fibrils, beta-amyloid monomers can also aggregate. The extracellular space between the neurons is then populated by the assembled insoluble fibrils, which form plaques. It was previously believed that amyloid plaques were poisonous and caused Alzheimer’s disease to develop. Over the last twenty years, research has indicated that beta-amyloid oligomers may be more harmful than amyloid plaques and may have a greater role in the onset of Alzheimer’s disease.
It is believed that decreased beta-amyloid protein synthesis or clearance is the cause of the buildup of beta-amyloid aggregates. Over the last twenty years, some medications have been created that either target the enzymes responsible for producing beta-amyloid or help to clear beta-amyloid aggregates. However, because of their serious side effects or inability to have the intended clinical effects, these medications have not been approved by the FDA. The only FDA-approved treatments that target beta-amyloid aggregates are the anti-amyloid antibodies aducanumab, lecanemab, and donanemab. The affinity of these antibodies varies for different kinds of beta-amyloid protein aggregates. While aducanumab and lecanemab bind to plaques, protofibrils, and beta-amyloid oligomers, donanemab binds to a particular form of beta-amyloid that is exclusively present in plaques. Whereas aducanumab has a higher affinity for insoluble fibrils, lecanemab exhibits the highest affinity for beta-amyloid protofibrils.
Activating an immune response against beta-amyloid aggregates and subsequently removing them is one of the proposed mechanisms by which anti-amyloid antibodies produce their therapeutic effects. Additionally, anti-amyloid antibodies may bind to oligomers and neutralize them, or they may destabilize the plaques. Aducanumab was given accelerated approval by the FDA in 2021 to treat Alzheimer’s disease because of its capacity to remove amyloid plaques. Aducanumab’s effects on cognitive function varied throughout clinical trials, despite its success in removing amyloid plaques from the brain.
A lack of evidence to support aducanumab’s therapeutic effects led to controversy surrounding the FDA’s approval process and a reluctance among prescribers to administer the medication. Furthermore, as was already mentioned, Biogen has halted aducanumab’s development and sales as of 2024. On the other hand, lecanemab and donanemab have demonstrated the capacity to remove amyloid plaques while delaying the course of the illness. Patients with early-stage Alzheimer’s disease and lower baseline beta-amyloid levels respond better to these treatments.
Lecanemab and donanemab may now be administered intravenously to patients with early Alzheimer’s disease, including those with mild cognitive impairment or mild Alzheimer’s disease, according to FDA approval. Whereas donanemab must be given every four weeks, lecanemab is recommended to be given every two weeks. The ability for patients to stop taking donanemab treatment once total plaque clearance has been achieved is one of its special features. Amyloid plaques accumulate over some years, and it is thought that people may need only limited additional care. Lecanemab and donanemab phase 3 trial participants demonstrated a 27% and 36% slower decline in cognitive function when compared to placebo, respectively. On the other hand, some researchers contend that these results are negligible and similar to the effects of symptomatic treatments, like acetylcholinesterase inhibitors, which treat symptoms but do not alter the course of the illness.
Moreover, the Clinical Dementia Rating Sum of Boxes (CDR-SB) was used to quantify the cognitive alterations mentioned above. Additionally, when evaluating the effectiveness of these anti-amyloid therapies based on the absolute difference in decline in cognitive function between the placebo and anti-amyloid antibody treatment groups measured directly in terms of difference in scores on the CDR-SB scale researchers found that the impact was not clinically meaningful. The Mini-Mental State Examination [MMSE], one of the more objective measures of cognition, only showed a 14.8 percent slower decline in cognitive function in those receiving donanemab treatment. Put another way, it has been suggested that the data that is currently available indicates that these anti-amyloid medications may only offer a slight clinical benefit.
Dr. Espay went on to say that the case for exorbitant costs is made by the safety concerns combined with negligible clinical benefits. What is considered a clinically meaningful effect, however, is still up for debate. According to some researchers, the amyloid cascade theory is supported by the therapeutic advantages of anti-amyloid antibodies. Some, on the other hand, contend that there are still a lot of unanswered questions and that this conclusion is premature. The amyloid-beta hypothesis states that Alzheimer’s disease should have progressed more slowly as a result of aducanumab’s capacity to remove plaques. Opponents counter that while aducanumab effectively removed amyloid plaques in trials, there were inconsistent positive clinical outcomes. Comparably, in patients enrolled in the phase III trial, donanemab eliminated approximately 85% of plaques but only caused a 14.8 percent slower decline in cognitive function, as determined by MMSE scores.
Crucially, the amyloid cascade theory served as the foundation for the FDA’s decision to approve aducanumab. The buildup of the tau protein within neurons is another aspect of Alzheimer’s disease, and the degree of tau accumulation—rather than beta-amyloid accumulation is linked to the severity of cognitive decline. Pharmaceutical interventions that aim to lower beta-amyloid levels or its production are capitalizing on the notion that beta-amyloid is a key factor in the development and advancement of Alzheimer’s disease. This theory has received a lot of criticism. Additionally, these drugs’ clinical trial results show a low level of efficacy and a high level of risk.
Because of this, some researchers contend that the modest efficacy of anti-amyloid antibodies suggests that the beta-amyloid pathway contributes to the development of Alzheimer’s disease along with other pathways, rather than showing that the beta-amyloid pathway plays a focal role in the disease’s development. This theory contends that Alzheimer’s disease is also influenced by a complex web of variables, such as those connected to the environment, oxidative stress, inflammation, metabolic variables, and genes unrelated to the amyloid pathway. This perspective also suggests that anti-amyloid medications may be used in conjunction with other treatments to treat Alzheimer’s disease.
On the other hand, beta-amyloid aggregation might be a byproduct of other malfunctioning biological pathways or a downstream phenomenon. It is now evident that metabolic dysfunction upstream of amyloid plaque formation is crucial for the activation of the brain’s microglial cells, and this phenotypic shift reduces beta-amyloid degradation while simultaneously enhancing its formation, according to Perlmutter. Furthermore, two key characteristics of Alzheimer’s disease are synaptic degradation and neuronal viability being threatened by microglial activation. As a result, treatments that target brain metabolism will probably be very beneficial for Alzheimer’s disease, as early research employing GLP-1 agonists has now shown, continued Perlmutter.
Anti-amyloid antibody therapies have modest clinical benefits, but their risks, costs, and accessibility must be considered before pursuing them. A considerable percentage of participants in the phase 3 clinical trials for lecanemab (45%) and donanemab (89%), experienced adverse effects. For example, individuals receiving anti-amyloid antibody therapy frequently exhibit brain alterations referred to as amyloid-related imaging abnormalities (ARIA). These alterations, which are detected on routine follow-up magnetic resonance imaging (MRI) scans, involve either small areas of bleeding from blood vessel rupture (microhemorrhage) or brain swelling (edema).
For example, in phase 3 trials, ARIA was observed in 21% and 38%, respectively, of patients treated with lecanemab and donanemab. The majority of ARIA cases have no symptoms and go away in ten weeks. Although the majority of ARIA cases have mild to moderate symptoms, there have also been reports of severe side effects, including seizures and even death. For example, in the phase III donanemab clinical trial, approximately 16% of participants had severe adverse effects associated with ARIA, while the donanemab group had a 0 point35% death rate.
The long-term consequences of amyloid-related imaging abnormalities, even when they are mild to moderate in severity, are unknown, which raises concerns beyond these serious side effects. Adverse reactions like nausea, fever, rash, and dizziness are also linked to the infusion of these anti-amyloid antibodies. Reactions related to infusion were noted in 24.7% and 8.7%, respectively, of patients receiving lecanemab and donanemab treatment. Frequent magnetic resonance imaging scans and clinical follow-ups are necessary due to amyloid-related imaging abnormalities and other side effects. In the phase III trials for lecanemab and donanemab, people with at least one copy of the APOE4 gene—a gene associated with an elevated risk of Alzheimer’s disease were more likely to experience brain swelling.
Additionally, these medications were less effective in people who carried one or more copies of APOE4. Thus, before starting anti-amyloid therapy, people must undergo genetic screening. Anti-amyloid immunotherapies are also linked to a decrease in the volume of the entire brain combined with an increase in the volume of the brain’s ventricles, which are spaces filled with fluid. Reduced cognition is linked to an increase in ventricle volume and a decrease in whole brain volume.
It’s unclear, though, if these modifications in brain volume and cognitive function are causally related. Therefore, it is necessary to investigate the effects of these modifications in brain volume following anti-amyloid therapies. It’s interesting to note that the hippocampus, a part of the brain important for memory and learning, saw a lesser decrease in volume following donanemab therapy. The likelihood of a few Alzheimer’s patients in the general population meeting the requirements to be enrolled in lecanemab or donanemab clinical trials is low. These studies involved younger patients with fewer co-occurring medical conditions. Treatment for a real-world population of people with co-occurring conditions and Alzheimer’s disease is therefore likely to result in a higher rate of adverse events or lower efficacy.
The identification and diagnosis of patients who qualify for anti-amyloid therapies presents another difficulty for the healthcare system, in addition to managing side effects. The majority of Alzheimer’s patients do not receive a diagnosis until later in the illness, and to identify the disease early, many people would need to be screened using imaging scans or biomarkers of the cerebrospinal fluid. Therefore, widespread availability would require a significant financial outlay for the detection and diagnosis of early-stage Alzheimer’s disease, APOE4 genetic testing, and the tracking and treatment of ARIAs and infusion-related reactions, regardless of their severity.
Certain diagnostic tests are needed to confirm eligibility for new treatment, and in the UK, one-third of dementia patients do not receive a diagnosis at all. To make sure that those who qualify for new treatments can receive them when they’re most effective which seems to be in the early stages of Alzheimer’s disease investments in diagnostic infrastructure and workforce are required. Lecanemab infusions cost about $26,000, while donanemab infusions cost about $32,000 per year. The price of genetic testing, screening and diagnosis, and tracking and controlling side effects are not included in this, though. However, there is a chance that new biomarkers for tracking treatment outcomes and improvements in diagnostic techniques will lower costs and increase accessibility to anti-amyloid medications.
References:
https://www.medicalnewstoday.com/articles/alzheimers-are-newly-approved-drugs-making-a-real-life-difference#Amyloid-cascade-hypothesis-and-Alzheimers-research