Pharmacy and Health Blog from myGenericPharmacy.com

In 2021, the Food and Drug Administration (FDA) finally approved some new medications to treat Alzheimer’s disease after a nearly two-decade hiatus. The majority of these medications are antibody treatments that target harmful protein clusters in the brain. 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. The neurodegenerative condition known as Alzheimer’s disease causes a slow and irreversible loss of thinking, memory, and ultimately the capacity to carry out daily tasks. Alzheimer’s disease is primarily caused by aging, and as the population ages quickly, it has become a public health emergency.

Alzheimer’s disease affected 57 million people worldwide in 2019; by 2050, that figure is predicted to rise to 153 million. This emphasizes the necessity of disease-modifying therapies that alter the course of the illness permanently and slow its progression. The development of disease-modifying treatments for Alzheimer’s disease, however, has not been successful until recently. The beta-amyloid protein, whose aberrant accumulation is generally thought to be the cause of Alzheimer’s disease, has been the focus of the majority of clinical research aimed at creating disease-modifying treatments for the condition. Regarded as the first disease-modifying treatment for Alzheimer’s disease, aucanumab, an antibody that targets amyloid-beta protein deposits, was approved by the Food and Drug Administration (FDA) in 2021.

Nevertheless, aducanumab’s manufacturer, Biogen, announced that it will eventually halt sales after clinical trials failed to yield consistent improvements in cognitive function. Since then, phase 3 clinical trials have shown that two additional anti-amyloid antibodies, lecanemab from Biogen and donanemab from Eli Lily, can slow cognitive decline in people with early-stage Alzheimer’s disease. These antibodies have been approved by the FDA. Clinicians and researchers have welcomed the approval of lecanemab and donanemab as a breakthrough after decades of clinical research that failed to yield effective disease-modifying therapies. The modest clinical benefits of these anti-amyloid treatments have, however, drawn criticism from some researchers who point to safety concerns and a lack of cost-effectiveness.

While there are challenges at the clinical, societal, and healthcare levels, we should not forget the opportunities and the breakthrough that after decades of very costly negative trials, we finally have unequivocal evidence that it is possible to reduce the progression of the disease, said Dag Aarsland, MD, professor of old age psychiatry at King’s College London in the United Kingdom, in an interview with Medical News Today. Paresh Malhotra, PhD, who teaches clinical neurology at Imperial College London in the United Kingdom, is comparable. K. pointed out that even though these anti-amyloid treatments are only moderately effective, it’s crucial to understand that they are the first to show clinical effects that seem to be connected to a major mechanism of disease progression. Their introduction could speed up the development of new treatments and revolutionize clinical services for Alzheimer’s disease, the most prevalent cause of dementia in the world.

The amyloid cascade theory is the foundation for the creation of anti-amyloid antibody therapies like lecanemab and donanemab. This theory states that Alzheimer’s disease develops as a result of additional alterations in the brain brought on by the buildup of beta-amyloid protein. In particular, it is thought that the development of beta-amyloid aggregates causes oxidative stress, inflammation, neuronal damage, the loss of synapses the connections between neurons that enable communication 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, deteriorates.

Secretase enzymes cleave a larger amyloid precursor protein to produce the beta-amyloid protein. Each beta-amyloid protein unit is known as a monomer, and these monomers can combine to form oligomers, which are soluble short chains made up of two to more than fifty monomers. Larger, soluble protofibrils and insoluble fibrils can also be formed by the aggregation of beta-amyloid monomers. In the extracellular space between neurons, the insoluble fibrils subsequently come together to form plaques.

Amyloid plaques were once believed to be poisonous and to be the cause of Alzheimer’s disease. However, over the last 20 years, research has indicated that beta-amyloid oligomers are more harmful than amyloid plaques and may be more involved in the onset of Alzheimer’s disease. It is believed that poor production or clearance of beta-amyloid protein is the cause of the buildup of beta-amyloid aggregates. Over the last 20 years, some medications have been created that either target the enzymes that produce beta-amyloid or make it easier to remove beta-amyloid aggregates. However, because of their serious side effects or inability to produce the intended clinical effects, these medications have failed to obtain FDA approval.

The only FDA-approved treatments that target beta-amyloid aggregates are the anti-amyloid antibodies lecanemab, aducanumab, and donanemab. The affinity of these antibodies for the different kinds of beta-amyloid protein aggregates varies. While aducanumab and lecanemab bind to beta-amyloid oligomers, protofibrils, and plaques, donanemab binds to a particular type of beta-amyloid that is exclusively present in plaques. While aducanumab has a greater affinity for insoluble fibrils, lecanemab exhibits the highest affinity for beta-amyloid protofibrils.

Activating an immune response against beta-amyloid aggregates and causing their removal is one of the hypothesized mechanisms by which anti-amyloid antibodies generate their therapeutic effects. Additionally, anti-amyloid antibodies may neutralize the plaques by binding to oligomers or destabilizing them. In 2021, the FDA gave aducanumab accelerated approval for the treatment of Alzheimer’s disease because of its capacity to remove amyloid plaques. Although aducanumab was effective in removing amyloid plaques from the brain, different clinical trials showed different effects on cognitive function.

The FDA’s approval process caused controversy, and doctors were reluctant to prescribe aducanumab because of the lack of evidence supporting its therapeutic effects. Additionally, as was already mentioned, Biogen has halted aducanumab’s development and sales as of 2024. On the other hand, lecanemab and donanemab have both demonstrated the capacity to remove amyloid plaques while delaying the course of the illness. People with early-stage Alzheimer’s disease and lower baseline beta-amyloid levels respond better to these treatments. The FDA has approved the intravenous infusion of lecanemab and donanemab for use in patients with early-stage Alzheimer’s disease, including those with mild cognitive impairment or mild Alzheimer’s disease.

Donanemab must be administered every four weeks, while lecanemab should be given every two weeks. Donanemab’s ability to allow patients to stop treatment once they have achieved total plaque clearance is one of its special qualities. Amyloid plaques develop over some years, and it is thought that people may only need minor additional care. Lecanemab and donanemab phase 3 trial participants demonstrated slower declines in cognitive function by 27% and 36%, respectively, when compared to placebo.

These results, according to some researchers, are mild and on par with symptomatic treatments like acetylcholinesterase inhibitors, which reduce symptoms without altering the course of the illness. Additionally, the Clinical Dementia Rating Sum of Boxes (CDR-SB) was used to measure the cognitive changes mentioned above. Additionally, when comparing the anti-amyloid antibody treatment groups to the placebo group, researchers found that the absolute difference in decline in cognitive function, as measured by the difference in scores on the CDR-SB scale, did not indicate a clinically significant effect of these anti-amyloid therapies.

Donanemab treatment only resulted in a 14–8% slower decline in cognitive function, according to more objective measures of cognition like the Mini-Mental State Examination [MMSE]. Stated differently, it has been suggested that the evidence currently available indicates that the clinical benefit of these anti-amyloid medications may be minimal. These medications’ effectiveness only results in a statistically significant but clinically meaningless slower decline rather than improvements. The clinical advantages of anti-amyloid antibodies, according to some researchers, support the amyloid cascade theory. Others, however, contend that there are still a lot of unanswered questions, making this conclusion premature.

The amyloid-beta hypothesis states that Alzheimer’s disease should have progressed more slowly as a result of aducanumab’s capacity to remove plaque. Nevertheless, detractors contend that aducanumab trials demonstrated efficient amyloid plaque removal without consistently yielding therapeutic benefits. Similarly, donanemab only caused a 14–8% slower decline in cognitive function as determined by MMSE scores, despite removing roughly 85% of plaques from patients in the phase III trial. Crucially, the amyloid cascade theory served as the foundation for the FDA’s decision to approve aducanumab. The buildup of tau protein within neurons is another aspect of Alzheimer’s disease, and the degree of tau accumulation—rather than beta-amyloid—is linked to the severity of cognitive decline.

The notion that beta-amyloid plays a key role in the development and progression of Alzheimer’s disease is being leveraged by pharmaceutical interventions that aim to reduce beta-amyloid or its production. Many people have contested this theory. Additionally, the outcomes of clinical trials for these drugs show a high associated risk and little efficacy. Therefore, some researchers contend that the modest effectiveness of anti-amyloid antibodies suggests that the beta-amyloid pathway contributes to the development of Alzheimer’s disease along with other pathways, rather than suggesting that the beta-amyloid pathway plays a focal role in the disease’s development.

This theory holds that Alzheimer’s disease develops as a result of a complex network of factors, including those linked to the environment, oxidative stress, inflammation, metabolic factors, and genes unrelated to the amyloid pathway. This perspective also suggests that anti-amyloid treatments, when used in conjunction with other therapies, may play a part in the treatment of Alzheimer’s disease. On the other hand, beta-amyloid aggregation might be a sign of other compromised biological pathways or a downstream phenomenon. According to Perlmutter, it is now evident that the activation of the brain’s microglial cells is largely dependent on metabolic dysfunction upstream of amyloid plaque formation. This phenotypic shift both promotes the formation of beta-amyloid and decreases its degradation.

Furthermore, microglial activation causes synaptic degradation and jeopardizes neuron viability, two key characteristics of Alzheimer’s disease. As has now been shown in early research employing GLP-1 agonists, treatments that target brain metabolism will therefore probably offer significant benefits for Alzheimer’s disease, Perlmutter continued. It is necessary to balance the risks, expenses, and accessibility of anti-amyloid antibody therapies against the limited clinical benefits they offer. A considerable percentage of participants in the phase 3 clinical trials for lecanemab (45%) and donanemab (89%) experienced adverse effects.

For example, amyloid-related imaging abnormalities (ARIA) are alterations in the brain that frequently occur in patients receiving anti-amyloid antibody treatments. These changes, which include either small areas of bleeding from blood vessel rupture (microhemorrhage) or brain swelling (edema), are seen during routine follow-up magnetic resonance imaging (MRI) scans. In the phase 3 trials, for example, ARIA was observed in 21 percent and 36 percent of patients treated with lecanemab and donanemab, respectively. The majority of ARIA cases are asymptomatic and go away in ten weeks.

Even though ARIA symptoms are usually mild to moderate, there have been reports of serious side effects like seizures and even death. In the phase III donanemab clinical trial, for example, approximately 1 in 6 participants experienced severe adverse effects related to ARIA, while the donanemab group experienced a death rate of 0 in 35. The long-term consequences of amyloid-related imaging abnormalities, even those that are mild to moderate in severity, are unknown, in addition to worries about these grave side effects. Adverse effects like nausea, fever, rash, and dizziness are also linked to the infusion of these anti-amyloid antibodies.

Of patients treated with lecanemab and donanemab, respectively, 24 and 8 percent experienced such infusion-related reactions. Regular MRI scans and clinical follow-ups are required due to these amyloid-related imaging abnormalities and other side effects. In the phase III trials for lecanemab and donanemab, people who had at least one copy of the APOE4 gene a gene associated with an increased risk of Alzheimer’s disease—were more likely to experience brain swelling.

Additionally, these medications were less effective in people who had one or more copies of APOE4. Therefore, before beginning anti-amyloid therapy, people must undergo genetic screening. Anti-amyloid immunotherapies are also linked to an increase in the volume of the brain’s fluid-filled ventricles and a decrease in the volume of the entire brain. Reduced cognition is linked to both a decrease in the volume of the entire brain and an increase in the volume of the ventricles. It’s unclear, though, if these alterations in brain volume and cognitive function are causally related. Therefore, it is necessary to investigate the effects of these alterations in brain volume following anti-amyloid therapies. It’s interesting to note that donanemab treatment led to a lesser decrease in the volume of the hippocampus, a part of the brain essential for memory and learning.

It is unlikely that many people with Alzheimer’s disease will fit the requirements to be enrolled in lecanemab or donanemab clinical trials. These studies’ participants were younger and had fewer co-occurring illnesses. Therefore, treating a real-world population of people with Alzheimer’s and co-occurring conditions is likely to result in more side effects or decreased effectiveness. The healthcare system faces additional challenges in diagnosing and screening patients who qualify for anti-amyloid therapies, in addition to managing side effects.

The majority of people with Alzheimer’s disease are not identified until the disease is advanced, and early detection would necessitate screening a large number of people with imaging tests or measuring biomarkers in cerebrospinal fluid. Therefore, widespread availability would require a significant financial outlay for APOE4 genetic testing, early Alzheimer’s disease screening, and diagnosis, and the monitoring and treatment of ARIAs and infusion-related reactions, regardless of their severity. A third of dementia patients in the UK do not receive a diagnosis at all, and certain diagnostic tests are necessary to confirm eligibility for new treatment. To make sure that those who qualify for new treatments can get them when they work best, which seems to be in the early stages of Alzheimer’s disease, we need to invest in diagnostic infrastructure and personnel.