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The Colombian writer Marquez wrote several paragraphs in his “One Hundred Years of Solitude”:

 

José Alkateo Buendia realized that insomnia had invaded the town and he called parents to tell them what they knew about amnesia. The people decided to take measures to prevent the disaster from expanding to other villages and towns in the Takizawa area. They took the small bells exchanged for Macaws and Arabs from the goat’s neck and placed them at the entrance to the town for use by visitors who insisted on entering the town in spite of sentry advice.

 

When his father uneasily told him that his most profound childhood memories had disappeared, Aureliano taught him this method. Jose Alcateti Buendia first implemented at home and then spread it to the town. He dipped in ink with a small brush to name everything: tables, chairs, clocks, doors, walls, beds, pans. He went to the corral to name animals and plants: cows, goats, pigs, hens, cassava, jellyfish, and bananas. As the study of all possible symptoms of amnesia continued to deepen, he realized that there would be a day when people could still not remember its function even if they could identify everything through labels. So he explained the details one by one. In this way, people continue to live in unpredictable realities, but once the meaning of the label’s text is forgotten, the reality that the words are temporarily maintained will eventually disappear.

 

Marquez made up the story of the Buendia family in “One Hundred Years of Solitude”. In this story, the residents of Makondo suffered from insomnia. There are many overlaps between the symptoms of insomnia and the conditions of Alzheimer’s disease.

We do not know whether this fictitious story is from Marquez’s life experience, but Marquez’s hometown of Colombia is indeed the place where the most severe of the family Alzheimer’s disease.

From the fifteenth to the seventeenth century, when Europeans crossed the Atlantic to the New World of the Americas, there were still some deadly diseases such as smallpox, measles, and yellow fever. But perhaps these Spanish conquistadors never expected to arrive in Colombia with them and Alzheimer’s disease.

 

The province of Antioquia in northern Colombia has the largest group of patients with familial Alzheimer’s disease in the world. A 2013 study showed that the mutation in the PSEN1 E280A gene that caused these people to develop familial Alzheimer’s disease was a Spanish conqueror more than 370 years ago.

 

By the 21st century, the conqueror still had 5,000 descendants. Of these, about 1,500 people carry this mutation. Because of carrying this mutation, these people eventually could not escape the fate of Alzheimer’s disease.

Alzheimer’s disease generally occurs only in the elderly group over the age of 65, and the average age of the family’s patients is only 45 years old. And usually only 8 years from the onset of symptoms to the death of the patient.

 

Drug development in the field of Alzheimer’s disease has been the hardest hit in clinical trials. For decades, there have been countless drugs entering clinical trials. But so far we have not found any drug that can stop the progression of the disease.

However, in these decades, our understanding of the disease has been constantly deepening. Perhaps research based on this group of Antioquia patients will provide new hope for the development of Alzheimer’s disease drugs.

 

The mystery of the amyloid hypothesis

 

Over the past few decades, hundreds of research drugs for Alzheimer’s disease have entered preclinical or clinical studies, and a large part of these drugs are designed based on the amyloid cascade hypothesis.

The amyloid hypothesis begins with a brain autopsy analysis after the death of Alzheimer’s patients. A very important feature of Alzheimer’s disease is the formation of plaque in the patient’s brain. Earlier, researchers discovered beta-amyloid protein in plaques. Later, based on the amyloid cascade hypothesis proposed by amyloid proteins, this hypothesis has always had a very important impact on drug development in this area.

The amyloid cascade hypothesis states that the accumulation of beta amyloid in the brain is a critical step in the pathological process of disease. The excess beta-amyloid protein present in the brain of the patient eventually aggregates and forms cellular effects such as chronic inflammation and oxidative stress.

Twenty years after the accumulation of amyloid protein in the brain, Tau protein function will begin to have problems, so that the Tau protein can not destabilize the cytoskeleton of neurons normally, and eventually the Tau protein will aggregate and form tangles. At this time, neurons begin to die and symptoms of dementia appear.

The amyloid cascade hypothesis has a lot of evidence to support, and with the increase of starch protein research, the theory of the amyloid cascade hypothesis seems to be more complete. Therefore, targeting starch proteins to develop drugs is also very reasonable.

There are many drug development strategies targeting amyloid proteins, but there are two main approaches. One of these strategies is to reduce beta-amyloid production by blocking BACE, an enzyme in the brain.

In addition to the development of BACE inhibitors, another highly focused strategy is to develop monoclonal antibodies that target amyloid proteins, thereby inhibiting the formation of plaque in the brain. The development of these two types of drugs is described in the article mentioned at the beginning of this article. It has already been stated that early clinical trials have shown that some drugs can indeed produce a certain degree of efficacy, but almost all failed in phase III clinical trials.

 

In February of this year, Merck stopped phase III of its BACE1 inhibitor Verubecestat (MK-8931). A few weeks ago, Lilly/AstraZeneca announced the termination of the development of its BACE inhibitor, lanabecestat. In January of this year, Pfizer decided to completely withdraw from Alzheimer’s disease after experiencing failures such as bapineuzumab.

Actually, it is not only a clinical study. There are also many difficulties in evaluating the pharmacodynamics of drugs in the field of amyloid protein.

Soluble beta amyloid oligomers are generally considered to be the most toxic form, but the problem is that there are many types of oligomers, such as these oligomers can be dimers, trimers, hexamers, twelve Conglomerates, and only hexamers already have five forms.

Not only that, these oligomeric beta-amyloid proteins also have problems because the polymerization process of these oligomers is highly concentration-dependent. If one tries to separate one of the oligomers, these polymers will form new ones. The equilibrium state produces new polymer forms.

In addition to the polymerization process, there may be differences in the starch proteins themselves. For example, different lengths of starch proteins with different chemical modifications can interact and bind to each other. And these structural differences also affect the polymerization process and the toxicity of the polymer.

 

Therefore, researchers often avoid molecular experiments when conducting drug research, and evaluate drug efficacy only at the cellular and animal level. However, there are also many defects in these studies, whether it is cell level or animal level experiments.

For example, in recent years, cells commonly used in experimental experiments are still tumor cell lines. Exogenous beta-amyloid protein is used to increase the intracellular concentration of amyloid protein and cause pathological changes. However, it is obviously unrealistic to mimic the pathological changes in the human brain that can last for decades. Animal models also have similar problems.

Therefore, even before entering clinical studies, it is difficult for us to have greater confidence in these drugs. However, these problems just increase the difficulty of drug development. Whether drugs can produce the desired efficacy still needs to be tested through clinical trials.

What is clear now is that at least for now, there is still no drug that can definitely slow down the progress of patients. What caused the failure of clinical trials of these drugs?

I believe no one can give an exact answer. However, there are indeed some theoretical attempts to explain this, and there are already some clinical trials that are currently validating these theories.

Hypothesis does not hold?

For the failure of clinical trials based on the amyloid hypothesis, many people give the explanation that the amyloid cascade hypothesis is untrue and wrong. It seems that all current large-scale clinical trial failures point to this point.

However, no matter whether the amyloid hypothesis is established or not, at least very early on, people have already realized that the word “cascade” in the amyloid cascade hypothesis is very inaccurate. Because obviously this is not a linear cascade. There are many negative feedback adjustments in this process. Moreover, the formation of inflammation and oxidative stress is not entirely due to the aggregation of amyloid protein.

The amyloid hypothesis is probably one of the biggest mysteries in the pharmaceutical field. As to whether the amyloid protein hypothesis really cannot be established, I don’t think it is time to conclude.

Better medicine?

After the failure of many drug phase III clinical trials, there are still many people who support the amyloid protein hypothesis because they feel that there is a big difference in the nature of these drugs currently in the late stages of research and development. These drugs can act on different forms of amyloid protein. The failure of some of these drugs does not mean that other drugs will also fail.

For example, many people think that solanezumab can target the extracellular soluble beta-amyloid monomer in the brain. The purpose of this antibody is not to remove plaques that have accumulated and form. Therefore, many people think that the failure of solanezumab will not affect the success of those antibody drugs that act on oligomers or plaques.

As for the banpineuzumab and Gantenerumab drugs targeting plaques, many people think that the failure of these two drugs is only due to dose problems.

Biogen did give high hopes to the company’s aducanumab. From the publicly available early clinical data, the drug did show some potential. However, whether it can succeed in phase III clinical trials is still unknown (Clinical trial: NCT02484547, NCT02477800).

In this reminder, verubecestat also published strong early data in 2016, which shows that the drug can effectively reduce the concentration of β40, Aβ42, and sAPPβ in human and primate plasma, brain and CSF. But in the end the drug did not produce the desired effect.

Early intervention?

In addition to these theories, it may be that the most popular theory about the clinical failure of these drugs is that patients can no longer use these drugs to intervene after they have developed symptoms. Starch protein aggregation began about 15 years before the patient developed symptoms, and these lesions have been difficult to repair after symptoms appear.

In order to be able to intervene earlier in the disease, researchers must try to find groups that are not yet symptomatic but who will develop after a decade or more.

It is clear that a familial group of Alzheimer’s patients like the patient population of Antioquia is a very good choice for this type of study.

And researchers can well predict the age at which these people’s diseases begin. Because these people carrying the genetic defect gene will eventually have the disease, and the age of the disease is close to the age at which their parents have symptoms.

 

The related DIAN trial will test the efficacy of two experimental monoclonal antibodies, ganneterumab from Roche and solanezumab from Eli Lilly in the FAD population. Although both drugs have previously failed in large-scale phase III clinical trials, these drugs may actually be effective against this patient population.

If this clinical trial can be successful, it will be a good thing for those affected by FAD. However, it is very successful, because the proportion of patients with familial Alzheimer’s disease is very small, and it is unknown whether more than 90 percent of the patient population is effective.

 

So now there are also researchers who are unwilling to wait for the results of the DIAN clinical trial. They hope to verify this theory in another way.

But before that, they must find a test to identify those groups that have not yet developed cognitive problems, but who will develop clinical symptoms in the next few years or decades.

For ordinary people, judging the difference between the brain of a patient who died of Alzheimer’s disease and the normal brain is not a difficult task. The brains of these patients have atrophy and are dotted with plaques produced by beta proteins and tangles formed by Tau proteins.

However, from the perspective of drug development, autopsy is clearly not a good diagnostic method, although it has been the gold standard for disease diagnosis for a long time.

While the patient is still alive, the doctor can only assess the condition of the patient through tests such as memory, but as mentioned above, when the patient appears, he has probably missed the best time for disease intervention. .

At the beginning of this century, researchers at the University of Pittsburgh inserted C-11 in the thioflavin T structure of the amyloid protein dye, resulting in Pittsburgh Compound B (PiB). The compound can be used for PET brain scans and can be very effective in screening patients. However, the half-life of this compound is very short, so after this there are some F-18-based compounds that have longer half-lives.

 

The application of this technology is very helpful for the screening of patients in clinical trials. In people over the age of 65, if there is no cognitive function problem but there is a cluster of amyloid protein in the brain, then it will be considered as a high-risk group for this disease.

The EARLY trail, which began in 2015, is testing the effectiveness of Janasen’s BACE1 inhibitor Atabecestat for this population (NCT02569398). The A4 clinical trial began in 2014 and evaluated Lilly’s solanezumab.

 

Given that it takes a decade or more from the onset of aggregation of amylogin to the appearance of symptoms of cognitive function, the duration of these clinical trials will be very long. The EARLY trial is expected to end in 2024.

 

Many of the drugs used in these early intervention clinical trials have been shown to reduce amyloid levels. If these clinical trials fail, it will also mean the end of the amyloid hypothesis.

Tau Protein Revival

 

In the decades since beta amyloid protein was discovered, the amyloid protein hypothesis has been a hot spot for new drug development in the AD field. However, with the failure of many targeted amyloid drugs, drugs targeting the Tau protein have begun to attract more and more in recent years. Much attention.

 

The pathological process of tau protein is also complex and involves multiple processes. Before the onset of symptoms, patients can see the pathological appearance of Tau protein in the brain, and neurofibrillary tangles occur later in the disease.

 

Before entanglement, Tau protein undergoes post-transcriptional modifications such as phosphorylation, abnormal acetylation, or changes in the length of Tau protein, resulting in a significant difference from the normal Tau protein. These processes are all potential targets for drug intervention.

 

Therapies targeting Tau proteins were initially focused on kinase inhibitors, Tau protein polymerization inhibitors, and microtubule stabilizers. The development of most drugs that target the Tau protein has been halted due to problems of ineffectiveness or toxicity.

 

However, most of the drugs currently in the field in the field belong to immunotherapy. Compared to amyloid protein, Tau protein has a stronger correlation with cognitive impairment, so after symptoms appear, Tau protein-targeted therapy may produce better efficacy than beta-amyloid-targeted drugs, at least. This is theoretically the case.

We also need to wait a long time to know if these drugs are really effective. It is indeed difficult to assess the prospects of most drugs in this area at present, but I still feel that the move from amyloid therapy to Tau-targeting therapy is not an improvement, but rather a failure after many failures.

Current status of clinical research on targeting Tau protein drugs

 

Targeted microglia

 

The impact of targeted frustrations on targeting of amyloid drugs has not only led some pharmaceutical companies to shift their research directions to the Tau protein research field. In fact, we can also clearly see that microglia research has gradually increased in recent years.

Although microglia have become a popular research area for Alzheimer’s disease, our understanding of microglia is still very shallow, which has greatly increased the risk of drug development in this area.

Microglia appear to be at the center of inflammation and neurodegeneration. Such cells can provide protection against neurons and their synapses, and they can also produce phagocytosis like other phagocytic cells. When microglia encounters abnormal cells/molecules such as beta amyloid or cell debris, it can be activated and cleared.

The research on the correlation between neuroinflammation and Alzheimer’s disease was very early, see the previous article. At that time, many non-steroidal anti-inflammatory drugs were found to fight Alzheimer’s disease and produce protective effects. However, clinical studies on COX inhibitors at the beginning of this century have not been successful. RAGE inhibitors also belong to the field of anti-inflammatory research and development of a new drug. But in April this year vTv Therapeutics announced that its phase III clinical trial of its RAGE inhibitor azeliragon has also failed.

However, the failure of these clinical trials clearly did not make people lose their enthusiasm for inflammation-related research. Two important studies in the 2013 New England Journal of Medicine found that certain TREM2 gene variants can significantly increase the risk of Alzheimer’s disease.

TREM2 in the brain is mainly expressed on the surface of microglia, so these studies also prompted people to start researching how to efficiently target microglia and regulate its function. However, inflammation in the brain is not always harmful, and inflammatory responses can also produce protective effects. In contrast to COX inhibitors, TNF inhibitors, or drugs that act on the IL-6, IL-2 pathway, microglial-targeted therapies may produce several different effects.

Although we are currently unclear about the function of microglia, at least there is already a lot of evidence that microglia can produce beneficial effects in the pathological process of the disease and can also produce harmful effects.

In the early stages of disease, microglia can monitor and eliminate dead cells, toxic amyloid plaques, and Tau entanglement. However, as the disease progresses, the scavenging ability of the microglia, which is continuously activated, may become less and less effective, but it will release harmful cytokines and cause damage to surrounding neuronal cells.

If this is the case, new drug developers must turn harmful microglia into favorable microglial cells. There is no doubt that this will not be an easy task, and Denali’s RIPK1 inhibitor is the first drug to validate this strategy. RIPK1 is downstream of the classical TNFR1 inflammatory pathway, and Denali believes that if RIPK1 is inhibited, it can inhibit inflammation and return microglia to a normal state.

Drugs targeting TREM2 can also regulate the function of microglia. However, compared with drugs targeting RIPK1, drugs targeting TREM2 can have different effects on microglia, because RIPK1 mainly regulates inflammation, and TREM2 can mediate microglia phagocytosis of dead cells in the brain and beta-starch. Protein capacity.

But the question is, should we improve this function or reduce the function of TREM2? At least in the study of animal models, different studies explained the function of TREM2 differently and even reached the opposite conclusion. Some studies have found that TREM2 in knockout mice is protective, while other studies have found that knocking out TREM2 can have deleterious effects.

 

A study published last year on PNAS showed that TREM2 can provide protection in the early stage of the disease, but it can promote the progression of the disease after the pathological changes of Tau. In other words, the function of TREM2 is phasic and produces different effects under different pathological conditions.

Therefore, it can be clearly seen that drug development in the field of microglia is not less difficult than other areas. Alzheimer’s disease is a very complex disease. With the current understanding of the disease and the current level of research and development of new drugs, it is almost impossible to reverse the disease after severe cognitive impairment.

Maybe aducanumab’s clinical trials can be successful, perhaps preventive trials can achieve the desired goal, if these drugs can be successfully listed, it is also a comfort for patients and their families.

Life is hard.

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