1 Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that predominantly affects the elderly and is characterized by memory loss, cognitive decline, and behavioral changes [1, 2]. Observed by participants with AD, patients have a four times higher mortality rate than those without dementia, with an average life expectancy of 6 years from the time of diagnosis. The data also reveal that, by the year 2024, AD will affect approximately 6 million people in America who are 65 years of age and older [3]. The disease is characterized by the formation of amyloid-β (Aβ) plaques and neurofibrillary tangles, which comprise hyperphosphorylated tau protein that adversely affects functioning neurons and causes cell death [4, 5].

Existing therapies for AD, including cholinesterase inhibitors, such as Donepezil, Rivastigmine, and Galantamine, offer only moderate efficacy and provide symptomatic relief without modifying the disease itself [6, 7]. Their benefits are short-lived, typically lasting 6–12 months, and they have side effects, such as nausea, vomiting, diarrhea, and fatigue, with limited effectiveness in the advanced stages of the disease. Similarly, inhibitors and N-methyl D-aspartate (NMDA) receptor antagonists like Memantine also provide symptomatic relief with short-term benefits and side effects like dizziness, headache, and confusion but are less effective in cases of mild cognitive impairment [8]. Anti-amyloid antibodies, such as Lecanemab (Leqembi [Eisai R&D Management Co. Ltd., Nutley, NJ]) [9] and Aducanumab (Aduhelm [Biogen, Cambridge, MA]) [10], show variable efficacy, and their use is complicated by risks such as amyloid-related imaging abnormalities (ARIA) and infusion-related reactions, along with high costs, which limit accessibility. Overall, these existing treatments have significant limitations, failing to halt disease progression and often struggling with the complexities of Alzheimer's pathology and the heterogeneous nature of patient symptoms. [11] However, donanemab emerges as a promising alternative, showing not only the potential to slow cognitive decline but also the ability to halt disease progression in some patients, particularly in the early stages of the disease. Its targeted mechanism and efficacy make it a notable advancement in the search for effective therapies for AD.

However, despite advances in studies, approaches to treating AD are scarce and mostly palliative, offering only moderate improvements. Currently used medications, including cholinesterase inhibitors and NMDA receptor antagonists, alleviate symptoms without treating or halting the disease. This limitation has compounded the search for disease-modifying strategies, especially those that address pathological changes in AD. To date, only two disease-modifying therapies have been approved for AD: lecanemab (Leqembi [Eisai R&D Management Co. Ltd., Nutley, NJ]) and aducanumab (Aduhelm [Biogen, Cambridge, MA]); however, the latter is no longer marketed. The requirement for further disease-modifying therapies is still significant because of the multifaceted and progressive nature of AD.

Donanemab is a monoclonal antibody that targets pyroglutamyl(3)-Aβ protein (3–42) to remove Aβ deposits and alter the disease course. One of its advantages is the opportunity to discontinue the treatment if the plaque is cleared. The U.S. Food and Drug Administration (FDA) has effectively approved the Kisunla (donanemab-azbt) injection for the treatment of AD in patients with mild cognitive impairment or mild dementia, in which the drugs were tested in clinical trials. Kisunla is given intravenously, and the recommended dose is given every 4 weeks [12, 13].

Thus, AD presents as one of the most complex neurological disorders with limited therapeutic interventions that can alter disease progression. Discoveries in the field of translational medicine offer novel therapies, with Donanemab serving as an example of successful targeting of Aβ plaques, which are considered one of the key pathophysiological features of AD [14]. This review aims to explore the history of donanemab from bench to bedside. Hence, through discussions on the mechanism of action, pharmacokinetics, and clinical use, we hope to gain a comprehensive understanding of the drug's use in the management of AD. Furthermore, we discuss the challenges and future prospects of donanemab to understand the real-world connections between basic and clinical research.

2 Donanemab's Mechanism of Action

Donanemab is a monoclonal antibody that targets a modified form of Aβ called N3pG found in amyloid plaques of AD, which comprises the accumulation of misfolded proteins [15, 16]. Through this interaction, it attaches to this particular epitope on amyloid plaques, resulting in the removal of amyloid plaques from the brain. Such an interaction causes microglial activation and enables plaques to be engulfed and cleared from the vicinity of neurons, as shown in Figure 1. This is because a decrease in amyloid deposition is expected to slow the progressive nature of AD [12]. On the molecular level, plaque clearance may eliminate the cause of synaptic pathology and reduce neuroplasticity, which are key components of total cognitive impairment in the disease. At the genetic pathway level, the action of donanemab could also affect the downstream signal transduction of APP processing, shifting the amyloid cascade for tau hyperphosphorylation and neurofibrillary tangles, which are the other pathological hallmarks of AD. The removal of amyloid by this process also leads to a decrease in the amyloid concentration in the whole brain. As a result, donanemab lowers the amyloid plaque load and averts the impact of amyloid toxicity that occurs in subsequent steps. This encompasses diminishing the inflammation elicited by a buildup of plaque, protecting other neurons from harm, and perhaps even halting, or at least the deterioration of, mental faculties tied to AD. Furthermore, a decrease in amyloid plaques may potentially stabilize or enhance synaptic functionality, which is necessary for cognitive processes. Donanemab is designed for patients with early symptomatic AD, either with MCI or with mild dementia stage of AD [17].

3 Pharmacodynamics and Pharmacokinetics of Donanemab

Donanemab is a monoclonal antibody that specifically binds and eliminates pyroglutamate-modified Aβ plaques in AD. It helps to remove these plaques by binding to them, thereby enhancing the activity of microglia, thus reducing the levels of amyloid deposition in the brain, as observed in 2024 clinical trials [18]. This reduction is associated with decreased rates of cognitive and functional deterioration in patients. It could also be postulated that donanemab influences tau, a subfacet of AD. However, it is linked with ARIA, including ARIA-E (edema), which necessitates close attention. However, these risks are counterbalanced by the fact that donanemab maintained plaque reduction over time and might have more dosing flexibility, furthering the drug's therapeutic promise [19, 20].

Donanemab is a humanized monoclonal antibody that has predictable pharmacokinetics and reaches peak plasma concentrations within hours of intravenous infusion. It is mainly localized in the plasma and extracellular space and penetrates the brain across the blood–brain barrier to bind Aβ deposits. As it is proteolytically cleaved into peptides and amino acids, donanemab is mainly eliminated through the reticuloendothelial system, the half-life of which ranges from 20 to 30 days. This permits dosing intervals of every 4 weeks or more. The pharmacokinetics of the drug do not change with age, and no dose adjustment is required in elderly patients. The key characteristics of donanemab are discussed in Table 1. Furthermore, donanemab does not involve the cytochrome P450 enzymes for metabolism and therefore is expected to have low potential for drug–drug interactions, which are desirable for the long-term treatment of AD [21].

4 Preclinical and Clinical Trials

Preclinical and clinical trials of donanemab have demonstrated its efficacy in reducing amyloid plaques and slowing cognitive decline in Alzheimer's patients, leading to its recent approval, and summary of preclinical and clinical trials for donanemab is given in Table 2. The Road map shows the summary of the donanemab development timeline as shown in Figure 2.

5 Efficacy, Safety, and Tolerability

In clinical trials, the efficacy of donanemab was proven to be effective in treating AD [17]. The main outcomes in the trials were mainly the degree of Aβ plaque deposition and the rate of cognitive decline using recognized clinical rating scales such as the CDR-SB and the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Donanemab achieved these primary objectives by presenting impressive differences in lowering amyloid plaques together with a potential decline in the rate of cognitive decline compared with placebo. Secondary outcome measures included activities of daily living and also global cognition, which all had better improvements in favor of donanemab demonstrating the ability of the patients to perform daily activities and quality of life [31].

Despite the promising results of donanemab, clinical trials have reported several side effects. Thus, side effects include mild to moderate infusion-related reactions, such as headaches, fever, and chills, which may only require some dose manipulation or symptomatic treatment. The serious adverse effect profile included ARIA, where one of the serious side effects observed was ARIA-E (edema) and ARIA-H (hemorrhage). Side effects in the form of ARIA events were reported in a large number of patients, especially at higher doses, but were mostly controllable by close monitoring and dose adjustment [32]. Thus, concerning ARIA symptoms, most of the cases did not have any symptoms at all or had only mild signs, while some of the patients had more severe reactions that required some sort of intervention. Other less common but more serious side effects were identified to be hypersensitivity reactions and serious infusion reactions [21, 33].

The management of ARIA with donanemab entails serial magnetic resonance imaging (MRI) to assess the emergence of ARIA symptoms. Self-report questionnaires and periodic physician examinations were the most prevalent tools for evaluating symptom severity. There have been changes in the dosage of donanemab based on ARIA, and symptomatic treatment involving corticosteroids may also be administered. Further, health education, including the diagnosis of ARIA and the timely reporting of any complications, is offered to the patients and their caregivers [34, 35].

In general, the tolerability of donanemab has been favorable and well-evidenced in clinical trials. From the reports by patients and observations made, most participants pointed to the ability to continue taking the treatment without interference from their normal lives. Although side effects associated with ARIAs were apparent, many of them were asymptomatic or only mildly expressed, and treatment with the drug was well tolerated with further application of adherent management measures [36]. The rate of serious adverse events was not very high, and the outcome of donanemab in reducing amyloid plaques and slowing the cognitive decline outweighs the side effects. The drug is considered to have a favorable tolerability profile when compared to other drugs that target amyloid based on the fact that the side effects are usually manageable by monitoring for such effects and intervening appropriately [37, 38].

6 Regulatory Status

7 Comparison With Existing Treatments

Compared with other Alzheimer's drugs, such as cholinesterase inhibitors and NMDA receptor antagonists, donanemab has unique features and efficacy profiles. Donepezil, Rivastigmine, and Galantamine are common cholinesterase inhibitors that act mainly by increasing the content of acetylcholine in the CNS, which improves cognitive function. However, they are only moderately effective, as they are basically used to treat the symptoms, and most of the time, the effects do not last for more than 6–12 months. These drugs were found to reduce dopaminergic cognitive decline only slightly with side effects such as nausea, vomiting, diarrhea, and fatigue and are relatively ineffective, particularly in the later stage of AD [46-48]. On the other hand, NMDA receptor antagonists such as memantine work by acting on glutamate, whereby they block it and provide symptomatic relief. Their benefits are similarly short-term; some data indicate that they may help delay cognitive decline in some patients, but the effect is likely to be moderated in patients with mild cognitive impairment. Data like dizziness, headache, confusion, and so forth also reduce their usage [49].

In contrast, studies have shown that donanemab selectively binds to N3pG amyloid plaques, slowing down cognitive deterioration by 32% and further arresting the disease in patients with early-stage AD. This disease-modifying ability makes donanemab superior to most existing treatments, which simply do not impact the disease's progression [21]. Though donanemab is associated with certain risks, including ARIA and infusion-related reactions, it is a step forward in treatment. Hence, the current use of cholinesterase inhibitors and NMDA receptor antagonists for treating forgetfulness primarily focuses on symptom alleviation, with no significant long-term effects on dementia reduction [37]. However, donanemab appears to be more effective in this context, as it initiates the process of altering the progression of AD and significantly slows down the worsening of dementia. Besides donanemab, other amyloid-modulating therapies such as lecanemab and aducanumab seek to alter the disease trajectory in patients with AD. Lecanemab, which targets amyloid protofibrils as illustrated in Figure 3 above, has been shown to slow down cognitive deterioration by 27% like other conventional drugs but cannot arrest the progression of the disease [39]. Aducanumab, while approved for its ability to reduce amyloid plaques, has produced mixed results in clinical efficacy, with some studies suggesting only variable cognitive improvement [10]. Both donanemab and Aducanumab have ARIA and infusion reactions, as does Lecanemab. However, given that donanemab acts differently and has different clinical outcomes, it may be a more effective medication to reduce further cognitive deterioration and stop the progression of the illness, which may be a significant advance in the treatment of AD. Table 3 shows a comparison of AD treatments: mechanisms, efficacy, and market status.

8 Challenges and Future Prospectives

Donanemab, a novel therapy for AD, has several advantages and risks. Although they demonstrated promising results in several clinical trials, the long-term safety and effectiveness of donanemab are still unknown because the data obtained are only based on a limited number of months starting from its approval in July 2024. The main effects of a treatment are rather different from one patient to another, depending on genetically mediated factors like APOEε4 and the type of AD; thus, it is challenging to predict who could benefit from the treatment the most. Moreover, the administration of donanemab through intravenous infusions poses significant challenges in terms of cost and method, particularly in settings with limited resources, raising concerns regarding health disparities. Other clinical concerns associated with the manifestation of lesions, such as ARIA-E and ARIA-H, might require dose adjustment or discontinuation of therapy due to the risk in elderly or more vulnerable patients. In addition, donanemab is under heavy competition from other newly approved anti-amyloid agents such as lecanemab and other existing symptomatic controls, which may reduce its market acceptance and contribute to the shift of AD therapeutic modalities. Regulatory issues are also, however, not fully resolved, since post-marketing surveillance may once again discover other safety issues or may result in a limitation of drug use. The strict biomarker-based patient inclusion, which requires access to imaging techniques such as amyloid PET and tau imaging, may impose restrictions on drug availability, thus curbing its role in the clinic.

There are bright perspectives in the future development of donanemab targeting various diseases, and among them is the perspective of its use in the concept of personalized medicine where the drug can be used in combination with other drugs according to the biomarkers and genetic characteristics of patients. Applying donanemab in synergy with other peripheral amyloid-clearing techniques that are in planning with targeted tau inhibitors or gene therapies may unveil the efficacy of the drug. Further research should focus on the effects of combination therapies using donanemab to address several pathological properties of AD to facilitate better treatment interventions. Further, we may also be able to explore new applications for donanemab beyond early symptomatic AD, including preclinical states, or in circumstances involving Alzheimer's with mixed features or vascular components. Potential enhancements in the method of drug administration, such as subcutaneous preparations or slow-release depot systems, may also help increase the use of donanemab given the inconvenience of infusions. With the enhancement of diagnostic tools, especially in biomarkers in the bloodstream and advanced imaging, the identification of potential patients for donanemab treatment may also become more effective and noninvasive, thus increasing the usage rate. Moreover, future studies, as well as the amass of longitudinal and real-world data, may even afford ways of fine-tuning the application of donanemab in actual clinical practice with risks reduced to a minimum while the benefits are simultaneously reaped to the fullest.

9 Conclusion

Donanemab has already been recognized as a game changer in the management of AD and is a clear example of successful translational medicine. Its development is a step forward in efforts to create a bridge from basic research to clinical application, providing new hope to Alzheimer's patients. In prior experiments conducted on animal subjects, treatment was found to be useful in eliminating amyloid plaques and moderate side effects. Furthermore, Phase I to III trials supported that donanemab had good potential in reducing cognitive decline and amyloid plaque accumulation. The risk factors of ARIA events and infusion reactions were predictable, and the drug was well tolerated. There has been enormous regulatory advancement because donanemab has gained full approval from both the FDA in April 2024 and the EMA in June 2024 due to demonstrable clinical value and safety. Compared with the currently available drugs, such as donepezil and rivastigmine, donanemab has been shown to exhibit better plaque regression and cognitive enhancement than other amyloid-targeted drugs, but with similar side effects. Future studies will focus on the enhancement of administration protocols, extension of the scope of application, and use of multiple agents. Any eventual loss of efficacy or adverse effects will likely be unveiled in follow-up investigations of donanemab, an essential piece in the Alzheimer's treatment puzzle. The ability to change the disease course, possibly in earlier stages, and perhaps in other neurodegenerative diseases, provides hope for better results. The combination of donanemab with superior biomarkers and imaging modes with further enhancements of gene and protein-centered editing places a new wave of precise prescriptions in Alzheimer's therapy. For these reasons, it is crucial to maintain the research focus and develop further to better comprehend AD and improve patients' outcomes, focusing on donanemab as a path to further neurodegenerative disease treatment.

Author Contributions

Nandhini Jayaprakash: writing–review and editing, writing–original draft, visualization, validation. Karthikeyan Elumalai: investigation, formal analysis, conceptualization.

Ethics Statement

Ethical approval was not required as this is a review of previously published studies.

Conflicts of Interest

The authors declare no conflicts of interest.