The development of new drugs for Alzheimer’s disease needs to adopt a holistic approach

“Scientific research always ascends in a spiral development process of negation of negation. When faced with new facts and contradictions that existing scientific theories cannot explain, it is necessary to change perspectives, propose further explanations and new hypotheses for their emergence and development. Through extensive observation, experimentation, and argumentation, these hypotheses become more complete and gradually evolve into systematic theories, which ultimately drive breakthroughs and evolution in science.”

Table of Contents

• Death is not the end; oblivion is
• Alzheimer’s disease is not a simple “single-cause disease”
• The research landscape for Alzheimer’s disease has shifted
• Is the Brain-Gut Axis the Confluence of All Cognition?
• Conclusion

Death is not the end; oblivion is

The world gradually becomes unfamiliar, until one day even one’s own face in the mirror is hard to distinguish, necessitating an anxious question, “Who is this?” This passage describes the “mirror sign” that some patients with advanced Alzheimer’s disease (AD ) may experience, where the patient mistakes their reflection for another independent person, or even thinks that there is an “intruder” in the house.

In fact, the memory impairment commonly perceived is just one manifestation of AD. As the disease progresses, the patient’s ability to perform daily activities will also gradually decline, and they may exhibit abnormal mental and behavioral symptoms.

Currently, the cause of AD is not clear, but according to past research data, the incidence of AD increases with age, which means that as our bodies gradually age, each of us could potentially be a patient with AD.

Alzheimer’s disease is not a simple “single-cause disease”

In the treatment of AD, there is a consensus in the medical community on early diagnosis and intervention.

The reason for advocating early treatment is also due to the fact that current treatment options for this disease are still limited. The vast majority of AD drugs on the market can only achieve limited improvement in patient symptoms or slow the progression of the disease. Stopping or even reversing the course of the disease remains a common hope in the field of AD drug research and development.

On July 26, 2024, Eastern Time, the EMA released the CHMP’s non-recommendation for the marketing authorization of the new AD drug lecanemab. According to the official EMA document, the CHMP’s reason for not recommending the marketing authorization of this drug is that the slight efficacy demonstrated by lecanemab is not enough to offset the risk of serious adverse events associated with the drug, that is, considering its clinical benefits less than the risks.

(Image source: official website of EMA)

This news has sparked widespread discussion in the industry because it means that this drug cannot be approved for marketing in the European Union. Lecanemab was approved by the FDA on July 6, 2023, but was required to carry a black box warning due to the risk of serious amyloid-related imaging abnormalities (ARIA).

The risk of ARIA is an issue that this drug cannot avoid. The Q&A document released by the EMA also pointed out: although most ARIA cases in its registration study were not serious, it cannot be ignored that some patients did have serious ARIA events, including cerebral hemorrhage, requiring hospital treatment. This is undoubtedly another significant challenge that cannot be ignored in the face of the global medical resource shortage.

In fact, the risk of ARIA is not only a problem for lecanemab, but all anti-Aβ monoclonal antibodies have this issue, including the recently FDA-approved donanemab from Eli Lilly, which also carries a black box warning for the same reason.

The aforementioned two drugs were both developed based on the mainstream theory of Alzheimer’s disease pathogenesis—the amyloid-beta (Aβ) cascade hypothesis. This hypothesis was proposed by Hardy and Higgins in 1992, suggesting that excessive production and aggregation of Aβ in the brain are the initiating factors for the onset of AD. In addition to the direct neurotoxic effects leading to neuronal damage, this process also activates other pathological processes (such as hyperphosphorylation of tau protein, synaptic damage, etc.), further exacerbating the disease progression in AD patients. Over the past few decades, the Aβ cascade hypothesis has dominated the research direction of AD and has attracted a large amount of scientific research funding and clinical trial resources.

The large-scale development of Aβ monoclonal antibodies was based on the 2006 publication regarding the impact of Aβ*56 (a subtype of Aβ) on the AD pathology in mice. In June 2024, this foundational, highly cited (nearly 2500 times) paper was admitted to be fraudulent by the corresponding author and was retracted. In response, Charles Piller, the investigative journalist from Science who first exposed this incident, sharply commented in The New York Times: this case has rendered many Aβ research papers meaningless and has not brought much hope to patients. Therefore, the theoretical basis for anti-Aβ monoclonal antibody treatment for AD has faced an unprecedented challenge.

On July 30, 2024, at the Alzheimer’s Association International Conference (AAIC), results from the Phase III Clarity AD study of lecanemab were announced. The study showed that over the 18-month core study, the lecanemab group had a 0.45 point reduction in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score compared to the placebo group (p=0.00005), indicating effective improvement in cognitive function.

However, after transitioning to the open-label extension study (OLE), the placebo group, which was treated for 18 months (this is a clinical design to verify disease-modifying drugs, namely the ‘delayed start’), showed no difference in disease progression from the previous 18-month double-blind period, with no inflection point in disease progression. Although compared to ADNI data, the lecanemab group had a 0.95 point reduction in CDR-SB score, its persuasiveness is not as strong as the conclusion drawn from the direct comparison with the placebo group.

(Image source: official website of Eisai)

Similarly, the Phase IIb clinical trial results of lecanemab showed that after 18 months of core study, followed by a 2-year gap period and then an additional 18 months of OLE, there was essentially no difference in the rate of disease progression between the lecanemab group and the placebo group (as shown in the Gap and OLE phases of the chart). This means that even though amyloid plaques in the brain have been cleared, 5 years of treatment did not change the course of the disease.

(Image source: official website of Eisai)

Looking at the clinical benefits and the latest clinical data from the two anti-Aβ monoclonal antibodies currently on the market, Aβ may not be the key target for treating AD.

When the light of hope that was once lit is extinguished again, the industry begins to rethink a question: what is the truth of AD?

AD is not a simple “single-cause disease,” as Charles Piller emphasized in his article. “Logically, if Alzheimer’s disease had a single and universal source, then this cause should have started to take effect earlier in an individual’s life and would show consistent characteristics in patients.”

“But the reality is, few age-related diseases have only one cause; it’s simply not logical,” said Dr. Matthew Schrag, a neurologist at the Vanderbilt University Medical Center.

It is also important to note that most clinically diagnosed AD patients not only have Alzheimer’s-specific pathologies (such as β-amyloid plaques and tau protein tangles) but also have comorbid pathologies not related to AD, such as vascular pathology, TDP-43 proteinopathy, and α-synucleinopathy.

A review published in Cell in 2023 mentioned that up to 90% of AD patients have comorbid pathologies not related to AD. These comorbid factors also affect the progression of the disease, which can further explain why in clinical trials, even though Aβ and tau proteins in the brains of patients have significantly decreased, the disease is still progressing.

(Image source: Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials)

In summary, the causes of AD are complex and diverse, and therapies that target only a single point are far from sufficient, a view that is gaining widespread support. Currently, the National Institute on Aging and the Alzheimer’s Association (NIA-AA) have jointly formulated the latest “Revised Criteria for the Diagnosis and Staging of Alzheimer’s Disease,” adding three new biomarkers to the classic ATN (A for amyloid-related biomarkers; T for tau protein-related biomarkers; N for neuronal or brain damage) framework: inflammation (I), vascular brain injury (V), and α-synuclein (S), namely the ATNIVS diagnostic framework. This reflects, from the side, that authoritative institutions have begun to re-examine the deeper causes of AD.

The research landscape for Alzheimer’s disease has shifted

AD is like an elephant; the real AD may be caused by a combination of factors including genetics, Aβ, tau protein, inflammation, oxidative stress, and metabolism. For a long time, the industry has tried to understand AD, but in the process of understanding, it has always been blindfolded.

Therefore, the conclusions drawn are often deviated from the truth. Like the blind men and the elephant, people are easily attracted to parts that are relatively more touchable, such as the elephant’s legs and trunk, corresponding to Aβ and tau protein in the field of AD, while the elephant’s back, which is not easily touched, is often neglected. In fact, these neglected areas are equally important.

Because only from a holistic perspective can we see the essence of the disease’s etiology. The above views come from a review titled “Re-imagining Alzheimer’s disease – the diminishing importance of amyloid and a glimpse of what lies ahead” in the Journal of Neurochemistry. The author uses the fable of the blind men and the elephant to objectively review the current state of AD research from a macro perspective.

Source of image: Re-imagining Alzheimer’s disease – the diminishing importance of amyloid and a glimpse of what lies ahead

“If many of the most influential scholars in this field had not reinforced the amyloid hypothesis with almost religious fervor, the solution to Alzheimer’s disease might have come sooner,” Charles Piller clarifies in the article.

Readers who follow AD should have noticed that the research strategy in this field is undergoing an unprecedented transformation, which can be reflected in the recently published review articles.

In April 2024, Professor Jeffrey Cummings, an authoritative clinical research expert in the field of AD, and his team published an article titled “Alzheimer’s disease drug development pipeline: 2024,” analyzing clinical trials related to AD as of January 1, 2024.

The article mentioned that, classified by drug target types, the number of all ADdrug clinical trials currently counted in order are neurotransmitter receptor drugs (28), neuroinflammatory drugs (25), drugs targeting Aβ (23), and drugs enhancing synaptic plasticity and neuroprotection (15), etc.

Based on this data, the number of clinical trials for AD drugs targeting Aβ no longer holds an absolute dominant position, and the number of clinical trials related to neuroinflammatory drugs has surpassed anti-Aβ clinical trials.

Data source: Alzheimer’s disease drug development pipeline: 2024. Image made by DrugTimes team

In addition, an article titled “Multi-target drugs for Alzheimer’s disease” published in Trends in Pharmacological Sciences in July 2024 pointed out a new strategy for the development of AD drugs: multi-target drugs. The article pointed out the complex multi-factorial nature of the causes of AD, believing that traditional therapies targeting a single target have failed, and new drug development needs to turn to multi-target drugs to achieve breakthroughs in clinical trials.

The author lists and analyzes several new drugs for AD under development in the article. These new drugs not only have their main target but also play other synergistic therapeutic roles. For example, some new drugs for AD mainly target Aβ and can also act on synaptic toxicity and inflammatory responses; there are also drugs that mainly target tau protein and also act on oxidative stress and blood vessels related to AD.

In fact, multi-target AD drugs are not a new concept, and even some products have been approved for marketing in China and have been included in the medical insurance catalog.

On November 2, 2019, the National Medical Products Administration approved the marketing of our country’s original new drug for AD, sodium oligomannate capsules (R&D code: GV-971). Sodium oligomannate targets the brain-gut axis. The brain-gut axis theory is a cutting-edge innovative theory in the field of AD research, and no other AD drug has been developed based on this theory before. Therefore, it was questioned a lot at the beginning of the market.

However, with the announcement of more relevant research results in recent years, the brain-gut axis theory has been continuously verified in AD research, and studies have shown that it is related to many pathogenic factors of AD. In addition, according to recent reviews, the new ATNIVS framework pathologic indicators are all related to the gut microbiota.”

Is the Brain-Gut Axis the Confluence of All Cognition?

In February 2024, Professor David M. Holtzman from Washington University in St. Louis and Professor Sangram S. Sisodia from the University of Chicago co-corresponded to publish a research paper titled “Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner” in Molecular Neurodegeneration.

The study concluded that sodium oligomannate can regulate the gut microbiota, inhibit the activation of reactive microglia, and reduce cerebral amyloidosis in a sex-specific manner in animal models, thereby changing the pathology of AD. It should be noted that this paper actually includes the conclusions of two different studies.

These two studies were conducted by two different research teams in different laboratories, using two different animal models and experimental designs, and there were also obvious differences in dosage and treatment time between the two experiments. In addition, it must be emphasized that before drawing conclusions, the two teams were completely unaware of each other’s experiments. However, since the conclusions were the same, the two teams decided to merge the results of both studies into one paper after consultation.

The significance of these two independent research conclusions lies in further verifying the brain-gut axis mechanism of action of sodium oligomannate.

As mentioned earlier, sodium oligomannate targets the brain-gut axis and is the world’s first new drug for AD based on this mechanism, promoting the research and development of the brain-gut axis theory.

The brain-gut axis refers to the two-way communication pathway between the brain and the gut microbiota, covering the nervous system, endocrine system, and immune system, including the hypothalamic-pituitary-adrenal axis (HPA axis), the sympathetic and parasympathetic nervous systems in the autonomic nervous system (vagus nerve), and the enteric nervous system in the gut, as well as the microbial community in the gut. This pathway is closely related to various neurodegenerative diseases and chronic diseases.

In 2021, researchers from the University of California published a snapshot article “SnapShot: The microbiota-gut-brain axis” in the journal Cell, detailing that the communication between the gut microbiota and the central nervous system can be achieved through at least three parallel and interconnected pathways.

Pathway 1: Neural. At the end of the 19th century and the beginning of the 20th century, a large number of studies made scientists realize that there might be a neural structure in the gut that is different from the central nervous system. This neural structure is now known as the enteric nervous system. The article points out that the gut microbiota can transmit local signals to the brain through enteric neurons, the vagus nerve, and spinal afferent nerves, participating in processes such as cognition, emotion, somatosensation, and feeding.

Pathway 2: Immune. There is a close interaction between the gut microbiota and the intestinal immune system. Metabolites and components of the gut microbiota can affect cellular immunity and humoral immunity, and act on microglia in the brain to regulate the brain’s immune system.

Pathway 3: Endocrine/Systemic. Metabolites and components of the gut microbiota can send signals through enteroendocrine cells and enterochromaffin cells in the gut, secreting various peptides and 5-HT, further regulating the hypothalamic-pituitary-adrenal axis. The endocrine axis can also feedback and regulate the gut endocrine through this method.

Image source: SnapShot: The microbiota-gut-brain axis

In addition, the brain-gut axis theory has been found to be related to various diseases other than AD. For example, a study published in the Journal of Neuroinflammation in 2023 mentioned that post-stroke cognitive impairment (PSCI) is also closely related to the brain-gut axis. The study analyzed the gut microbiota of 34 PSCI patients and 49 non-PSCI patients and found that the levels of Enterobacteriaceae and lipopolysaccharides in PSCI patients were significantly increased. Further experiments with mice confirmed that the gut microbiota is directly related to the onset of PSCI.

More studies have proven that the brain-gut axis, as a biological channel connecting the brain and the gut, plays an important role in the occurrence and development of neurodegenerative diseases. In addition to central system diseases, cardiovascular diseases, metabolic diseases, and liver diseases are all accompanied by cognitive disorders, and these cognitive disorders are all related to the brain-gut axis.

So, a proposition has been put forward, that is, “Is the brain-gut axis at the confluence of all cognition?” The repeatedly mentioned gut microbiota is the core role when the brain-gut axis theory is applied to the treatment of specific diseases, and its connection with AD has been verified by multiple studies.

In January 2024, Professor David M. Holtzman published an article titled “Current understanding of the Alzheimer’s disease-associated microbiome and therapeutic strategies,” systematically summarizing the current scientific understanding of the role of gut microbiota in the pathogenesis and treatment of AD.

The article first proposed the concepts of “healthy brain-gut axis” and “Alzheimer’s disease brain-gut axis.” It pointed out that aging, diet, and long-term intake of drugs/alcohol can lead to the disorder of the gut microbiota, transforming the normal brain-gut axis into the Alzheimer’s disease brain-gut axis. These biological processes ultimately lead to neuroinflammation in the brain, thereby causing the development of AD pathology.

The author’s above arguments have been directly or indirectly proven by many previous research results. For example, past studies have found that as AD progresses, the composition and diversity of the gut microbiota in patients change. There are also studies showing that compared with healthy people, the Firmicutes and Bifidobacterium in the gut of AD patients are significantly reduced, while the Bacteroidetes are increased.

In addition, a study titled “Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease” published in Science Translational Medicine in 2023 showed that the gut microbiota of patients had already changed before the clinical symptoms of AD appeared, and it was related to Aβ and Tau .

The study included 164 cognitively normal individuals (49 of whom had evidence of preclinical Alzheimer’s disease biomarkers), and the analysis of their gut microbial taxonomic characteristics found that the gut microbial taxonomic characteristics of preclinical AD patients were different from those without evidence of preclinical AD, and further analysis found that the composition of the patient’s gut microbiota was related to Aβ and tau PET.

These studies convey an important signal to the industry that the gut microbiota is crucial for maintaining healthy brain function. The “Expert Consensus on Simple Screening for Preclinical Alzheimer’s Disease in China (2023 Edition)” also pointed out that a specific combination model of gut microbiota and metabolites can be used to predict AD.

Most importantly, the article published in Science Translational Medicine proposed an exciting speculation for the entire field of AD: targeted intervention of the gut microbiota can reverse or improve the pathology of AD, and introduced the brain-gut axis intervention mechanism with sodium oligomannate as an example.

Reversing the course of the disease is the ultimate goal of people’s exploration of AD diagnosis and treatment. Currently, this speculation has been preliminarily verified by the latest research results of sodium oligomannate.

It is known that two post-marketing clinical studies of sodium oligomannate, GV-971-PMS-A and GV-971-PMS-B, have observed the long-term safety and efficacy in 3300 patients for 2 years. Preliminary interim analysis results show that for patients with newly diagnosed AD, cognitive function and daily living ability have been improved above the baseline after 48 weeks (all patients completed follow-up) and 96 weeks (partial patients completed follow-up) of monotherapy with sodium oligomannate, thus showing the potential to reverse the course of the disease.

Another highlight of this study is that the enrolled patients are very consistent with the characteristics of real-world AD patients. It is reported that among the 3237 patients enrolled in the two studies (78.6% of patients over 65, 59.5% female), patients have other common elderly diseases (hypertension 52.4%, diabetes 22%, hyperlipidemia 31%, coronary artery disease 16.4%, stroke 32.8%, sleep disorders 13%), and patients have common elderly medication co-use (antihypertensive drugs 49.6%, hypoglycemic drugs 20.8%, lipid-lowering drugs 42.3%, antiplatelet drugs 34.4%, sedative/hypnotic drugs 22.3%, cardiovascular drugs 19%), the condition is complicated, and it is highly consistent with the real situation of AD patients in the clinic.

The study results also show that sodium oligomannate has good safety and tolerability, and there is no potential safety risk under the common co-use of elderly diseases and commonly used elderly drugs.

Conclusion

The origin of medicine stems from the initial human desire to express and alleviate suffering. Over time, as understanding of diseases deepened and medical diagnostic and therapeutic tools evolved, the treatment of diseases in clinical practice gradually became more refined and specialized.

However, the highly specialized perspective on treatment sometimes may deviate from the most fundamental needs of the patient, leading to fallacies such as “blind men touching an elephant” or “treating the symptom rather than the cause,” which introduces epistemological and methodological doubts and deviations in the study of human life and the prevention and treatment of diseases. This serves as a reminder to return to the starting point and view the problem holistically.

Considering the patient as an individual who longs to return to a healthy life, rather than a person with a specific disease, is especially critical in correcting the concept of disease treatment for complex diseases like AD.

“It’s time for the field to move forward,” Dr. Schrag said, echoing the collective voice of millions in the industry.

【Editor’s Note】This is a quick translation of the Chinese article by DrugTimes team. To view the original article, please click here . All comments are warmly welcome. Many thanks!