On the ruins of memory

The present and future of Alzheimer's disease

Viktor Lebedev, "Biomolecule"

"We need to start losing memory, albeit partially and gradually, in order to realize that our being consists of it. Life outside of memory is not life at all." These words belong to the famous director Luis Bunuel, whose mother suffered from dementia at the end of her life. The gradual but inevitable loss of memory, and with it personality, can frighten everyone. What can modern science offer to combat this terrible disease – Alzheimer's disease?

* * *

Ekaterina Pavlovna was born in 1947. She graduated from a construction school, worked as a painter-plasterer, and after retirement began working as a janitor in a hostel. At some point, she got tired of it, and she quit working. A year later, her husband died of a heart attack. Ekaterina Pavlovna has a daughter, Elena, and a son, Pavel. They had already got their own families, and on weekends, when the work schedule allowed, a large family visited my grandmother in her apartment in a residential area of the city.

The character of the article is fictional. However, this does not negate the fact that there are thousands of stories like this one.

Everything went on as usual, until relatives noticed the appearance of some oddities in the behavior of Ekaterina Pavlovna. Daughter Elena began to notice that expired products are often in the refrigerator, and her mother is trying to cook something from them, not understanding the inconsistencies in the dates. Dinners were gradually simplified, and then completely tasteless. All sorts of junk began to accumulate in the house, and mom herself wore the same things for a long time, even if they became dirty. Ekaterina Pavlovna increasingly forgot recent events: she could leave home when she and her daughter agreed to meet in the apartment, she was confused about dates. She started calling Elena's husband brother. He blamed everything on senile oddities, and Elena agreed with him.

One day Elena asked Ekaterina Pavlovna to put the kettle on. An elderly woman took an electric kettle, put it on the stove and began to strike matches, lighting the gas. Elena rushed to her mother and stopped her. It became clear that this could not continue. After talking with friends and studying information on the Internet, Elena realized that Ekaterina Pavlovna needed a doctor. Fortunately, there were several doctors in their city who specialized in such disorders. At the reception, the doctor talked for a long time with Ekaterina Pavlovna, asked questions to his daughter. Finally, he asked Ekaterina Pavlovna to leave the office and informed Elena that her mother probably had Alzheimer's disease.

The fading sun of Memory

Alzheimer's disease (AD) is a neurological disease based on atrophy of the hippocampus, parietal and temporal cortex of the brain. The main manifestation of the disease is dementia, that is, a progressive decrease in cognitive functions (attention, memory, intelligence), which leads to the loss of social and household skills, up to the loss of the ability to self-care. There are other neurological and mental symptoms of the disease, but they have a lesser effect on the patient's condition.

Dementia in Alzheimer's disease has a number of features that distinguish it from other types of dementia. Alzheimer's dementia, even in the early stages, significantly affects a person's biographical memory. The patient has distortions and loss of memories. This applies even to the most important points: the names and number of children, the death of loved ones. A catastrophic loss of a person's entire past experience, the destruction of his personality, is taking place before his eyes.

In addition, skills (praxis) and the ability to perform even simple actions are quickly lost. This symptom is called apraxia. The patient's ability to recognize objects and recognize people is also reduced (agnosia). In addition to this, specific speech disorders occur: words and syllables are replaced by similar-sounding ones. Over time, speech becomes less coherent and eventually may be completely lost (aphasia). The complex "aphasia-apraxia-agnosia" with a high probability indicates Alzheimer's disease. The result of the development of the disease is a complete loss of the patient's ability to serve himself, including eating independently, moving around and controlling pelvic functions.

The ICD-10 separates the forms of dementia in Alzheimer's disease with early and late onset (Fig. 1). Dementia in AD with early onset is characterized by a debut before the age of 65, a faster course and a predominance of symptoms of aphasia-apraxia-agnosia. Early onset is more often associated with a family history of the disease. If a person suffers from this form of Alzheimer's disease, then the risk of getting sick in his children is about 50%. Dementia with AD with a late onset manifests itself after 70 years and proceeds more slowly, with predominant memory damage; the disease occurs sporadically (accidentally).

Figure 1. Distribution of patients with Alzheimer's disease in the United States by age group. Patients under the age of 65 make up only 4% of the total number of cases (Alzheimer's Association: 2016 Alzheimer's Disease Facts and Figures).

According to scientists, the older a person is, the higher their risk of getting AD (Fig. 2). American researchers predict a significant increase in the number of cases of Alzheimer's disease, as the population of developed countries (including the USA) continues to age (Fig. 3) [1].

Figure 2. The risk of Alzheimer's disease during life. At the age of 65, the risk of developing AD in women is 21.1%, that is, every fifth woman who has reached this age becomes ill. Among men, about one in ten develops AD. The older a person is, the higher the risk of developing dementia (Alzheimer's Association: 2016 Alzheimer's Disease Facts and Figures).

Figure 3. Expected increase in the number of patients with Alzheimer's disease in the USA [1].

The life expectancy of the population is increasing, respectively, and the number of elderly and senile people is growing. Each of us has a high chance of living to the age of over 65. In this age group, approximately one in ten suffers from Alzheimer's disease, and women have twice the risk of getting sick. And if we take a group of people aged 85 and older, then every third person in it will be ill. Advances in medicine have prolonged a person's life, but have led to the fact that a new problem is gaining momentum – Alzheimer's disease, for which there is no effective cure. People began to die less from cardiovascular and oncological diseases. The vacant place was quickly occupied by Alzheimer's disease (Fig. 4). The older a person gets, the higher the probability of developing this disease and dying from it (Fig. 5).

Figure 4. The increase in mortality from Alzheimer's disease in the United States in the last 30 years. The number of deaths from AD in comparison with deaths from other diseases is reflected. ICD – International Classification of Diseases. The number in the circle is the place occupied by a particular disease in the ranking of the leading causes of death in 2013 (Deaths: Final Data for 2013).

Figure 5. Mortality from Alzheimer's disease in different age groups. Data for each of the 10 leading causes of death are given as a percentage of the total number of deaths. HZNDP – chronic diseases of the lower respiratory tract. To see the drawing in full size, click on it (Deaths: Leading Causes for 2014).

Currently, there are 47 million patients with dementia in the world and more than 7 million new cases of the disease are recorded annually. Two–thirds of these figures are the contribution of Alzheimer's disease. 5.5 million patients with this diagnosis now live in the United States. The approximate number of Russians suffering from asthma is estimated at at least one million people. The counting of patients in our country is complicated by the fact that there is no separate register for this disease. In recent years, all researchers of Alzheimer's disease agree that the number of patients with this disorder will increase along with the life expectancy of the population, and Russia will not be an exception to this global trend. By 2030, the incidence is projected to reach 75 million cases worldwide, and by 2050 - 132 million. However, there is an alternative point of view in the scientific community, supported by statistics, according to which there is no such catastrophic increase in the incidence of AD. Some researchers believe that we can even talk about a decrease in the number of cases of dementia (at least in the USA [2]), and attribute this to the increased level of education of the population. Time will tell who was right.

Inside the head

Ekaterina Pavlovna's illness did not begin at the moment when she began to get confused about the shelf life of products, but several years earlier. This is known due to long-term observations using positron emission tomography (PET) of the brain of elderly people. Characteristic histological signs of Alzheimer's disease are β-amyloid plaques and neurofibrillary tangles in the cerebral cortex. β-amyloid is known to arise from a specific precursor protein (APP). In the neuron, APP is cut by enzymes and turns into β-amyloid, clusters of which can be seen under a microscope (Fig. 6b). Its function is not completely clear, but it is known that β-amyloid has antimicrobial activity [3], [4], [5] and participates in the realization of innate immunity [6]. Neurofibrillary tangles consist of hyperphosphorylated tau protein (Fig. 6a) [7]. The function of tau protein normally consists in stabilizing microtubules in the axons of neurons and ensuring the normal transport of substances inside the neuron. Studies show that the appearance of clusters of tau protein can be caused by the influence of β-amyloid interfering with the work of axonal transport [8].

Figure 6. Histological signs of Alzheimer's disease. a – clusters of tau protein; b – amyloid plaques [7].

Based on the data on β-amyloid, the amyloid hypothesis of Alzheimer's disease was put forward. Changes in cognitive status were directly associated with the accumulation of this protein in the tissues of the human brain. However, now in the scientific community, the beta-amyloid hypothesis is being expressed more and more cautiously. In one of the articles on this topic, the authors wrote that β-amyloid seems to be necessary, but not sufficient to start BA [9]. You can read more about the pathogenesis of Alzheimer's disease on Biomolecule in the article "Death after life, Alzheimer's disease and why we want change" [10].

According to recent data, the prevalence of extracellular beta-amyloid deposits in the cerebral cortex correlates with cognitive decline less than the number of tau protein accumulations inside cells (Fig. 7). In addition, the sequence of tau protein appearance in various parts of the brain correlates with the occurrence of certain symptoms of Alzheimer's disease. In the initial stages of the disease, short-term memory suffers the most, and at the same time neurofibrillary tangles are found in the hippocampus. With the further development of the disease, visual perception and executive function disorders occur, which correlates with the appearance of tau protein in specialized parts of the brain.

Figure 7. Correlation of cognitive decline in MMSE scores with the prevalence of neurofibrillary tangles (a) and amyloid plaques (b). The correlation coefficient with cognitive decline measured by the standard MMSE test is higher in the case of tau protein [7]. With a broader view of the problem of Alzheimer's disease, scientists have put forward other candidates for the role of the "main villain", for example, the APOE gene, more precisely, its E4 allele [11]. The variability of this gene is important for the sporadic (random) form of Alzheimer's disease. The owners of the E4 variant of apolipoprotein E have an increased risk of developing Alzheimer's disease, atherosclerosis, an unfavorable outcome of brain injury and rapid progression of multiple sclerosis. In the brain, ApoE is involved in cholesterol metabolism and immune response. How ApoE4 is related to Alzheimer's disease is not fully understood, but recent studies give hope for a speedy resolution of this mystery. The ApoE4 isoform, binding to a receptor on the surface of a neuron, causes more active beta-amyloid production than the ApoE2 and ApoE3 forms [12]. This discovery is particularly interesting, since molecules that can make ApoE4 similar to ApoE3 (ApoE4 structure correctors, apoE4SCs) are already being developed.

Diagnostics

In order to assume the development of Alzheimer's disease in a patient, it is not necessary to do a lifetime biopsy of the brain. There are safer diagnostic methods: neuroimaging and biomarker search.

The PET mentioned earlier has a number of disadvantages: isotopic preparations for PET are not readily available in small towns, the life span of the isotope is small (and for this reason it cannot be transported over long distances), there is also a problem of marker specificity (different labeled substances are needed to determine different signs of AD – for example, PET with labeled glucose reveals a metabolic disorder in the departments the brain responsible for learning and memory).

Another diagnostic method may be magnetic resonance imaging (MRI) of the brain with an assessment of various indicators of its structure. Currently, we can assess the degree of atrophy of the hippocampus and the cerebral cortex. These indicators reliably indicate current Alzheimer's disease [13]. Neuroimaging is valuable because it allows you to identify reversible forms of dementia (tumor, normotensive hydrocephalus). Neurosurgical intervention in such cases will help the patient quickly and effectively.

Laboratory tests can also confirm the diagnosis of Alzheimer's disease: for example, it is possible to measure the levels of tau protein and β-amyloid in cerebrospinal fluid [14] or blood plasma [15]. Well, you can also do a genetic analysis – determine your own combination of APOE gene alleles inherited from your parents.

Medicine for the mind

After Ekaterina Pavlovna was diagnosed with Alzheimer's disease, the doctor prescribed her treatment in accordance with modern recommendations. Despite an incomplete understanding of the molecular foundations of AD, we can say for sure that the activity of the acetylcholine system of the brain decreases with this disease (you can read about the role of acetylcholine in human life on our website [16]), and this has been known since the 1970s [17]. That is why the acetylcholine system has become the main target of AD therapy.

The first drug for Alzheimer's disease was takrin (Cognex, Pfizer), approved by the FDA for use in 1993, but 20 years later it was no longer used in clinical practice, as new drugs appeared. Takrin belongs to cholinesterase inhibitors (IHE): its action increases the amount of acetylcholine in the brain of patients with AD. Currently, three IHE are used: donepezil, rivastigmine and galantamine.

In 1996, donepezil (Aricept, Pfizer) went on sale in the USA, and later its use was approved in other countries. The drug is considered effective against dementia in Alzheimer's disease of any severity [18]. According to the latest data, the volume of global sales of donepezil exceeds $ 4 billion: now it is the most prescribed drug among the IHE.

A year after donepezil was approved, rivastigmine (Exelon, Novartis) was released in Switzerland, which also showed good results in the treatment of Alzheimer's disease [19]. Rivastigmine can be found on sale in capsules or solution, as well as in the form of a transdermal therapeutic system, TTS. Galantamine (Reminyl, Janssen-Cilag) began its journey in Sweden in 2000, entered the markets of other European countries, and later reached the USA. Galantamine has proven efficacy against BA [20].

IHE affect their target – the enzyme cholinesterase – in different ways, so if one of the drugs in this group has proved ineffective, the doctor may prescribe another. But all IHE have similar side effects, which are caused by the effect on the cholinergic system of the body. IHE can slow down the heart rate, which is potentially dangerous for people with blockages of the heart's pathways and a tendency to bradycardia. Frequent reactions to taking HE inhibitors include nausea and vomiting, which is very poorly perceived by patients and caregivers. Another characteristic side effect is weight loss [21]. Patch (TTS) with rivastigmine causes fewer adverse reactions from the gastrointestinal tract. At the same time, the TTC ensures uniform release of the drug without a sharp increase in the concentration of the drug in the blood. Sometimes rivastigmine in the form of TTS causes skin irritation, which prompts you to stop using it. In addition to Alzheimer's disease, IHE is used in the treatment of dementia with Lewy bodies and dementia in Parkinson's disease.

In addition to the three listed drugs, memantine (Akatinol, Merz) is available to doctors. This drug affects the glutamate system of the brain by blocking NMDA glutamate receptors [22]. According to modern research, memantine at a dose of 20 mg/day can be considered an effective treatment for Alzheimer's disease [23]. Sometimes doctors recommend using a combination of memantine and one of the IHE. Evaluation of the effectiveness of combination therapy showed that the combination of drugs of the two groups has a slightly more pronounced positive effect on the cognitive status and daily functioning of the patient in comparison with the isolated use of IHE [24]. It may also be necessary to connect neuroleptics (for example, risperidone) to the therapy of AD – to correct behavioral disorders or psychosis. It is obvious that the combination of anti-drug drugs or the addition of antipsychotics to them leads to an increase in the cost of therapy (Table. 1), but unfortunately, this is not always rewarded with long-term improvements.

Table 1. The cost of treating Alzheimer's disease with basic drugs. Prices are given according to the website zdravzona.ru as of 12.03.2017

The criterion for the effectiveness of dementia treatment in AD is considered to be a slowdown in the rate of cognitive decline, which is evaluated according to the standardized MMSE or MoCA test scales. If, against the background of taking the drug, the patient's MMSE scores stop decreasing (or at least the process slows down), this is considered an undoubted success of therapy. Also, the effectiveness criteria include reducing the frequency of behavioral disorders (leaving home, irritability attacks) and maintaining the patient's independence in terms of self-service. These indicators can also be measured on special scales.

The same methods are used to evaluate the effectiveness of the drugs being developed. If a new drug turns out to be no better than the existing ones, they stop doing it. Often, the doctor does not observe an improvement or stabilization of the cognitive status, but relatives note positive dynamics in the patient's behavior. Drugs used for the treatment of Alzheimer's disease can delay the loss of independence and slow down the rate of decline in the cognitive functions of the patient. At the same time, they are not able to prevent the disease or reverse its course.

In Russia, patients with Alzheimer's disease have the opportunity to receive IHE (galantamine and rivastigmine) for free. Healthcare institutions can purchase them within the framework of the Supplementary drug Supply Program (DLP), but the choice of the drug for purchase takes place within the medical institution itself. So Ekaterina Pavlovna, after completing the necessary documents, began to receive medicines at the local neuropsychiatric dispensary.

The Future of therapy

If we talked about modern means of therapy above, then here we will talk about the prospects for the treatment of Alzheimer's disease. Alas, so far they are completely bleak: over the past 14 years, not a single new drug for AD has appeared, and the search for such drugs is gradually turning into a cemetery of hopes. Ekaterina Pavlovna will receive symptomatic treatment that will slow down, but not stop the process. Sooner or later, the disease will take its toll, and the patient will gradually fade away. If anyone can get an effective cure for Alzheimer's disease, it will be representatives of the next generations of Ekaterina Pavlovna's family. Although there is no confidence in getting an effective drug soon.

The last FDA-approved treatment for Alzheimer's disease was memantine. It happened in 2003, and 14 years have passed since then... Currently, almost 100 BA drugs are being investigated. Beta-amyloid, tau protein and the inflammatory process in the central nervous system were chosen as their main targets. Drugs with other mechanisms of action are also being tested, which reflects the multiplicity of unconfirmed hypotheses regarding the molecular basis of the disease. It seems that scientists are trying to adapt everything they can guess to the therapy of Alzheimer's disease (Fig. 8).

Figure 8. Drugs being developed to combat Alzheimer's disease. Most of the drugs are undergoing the second stage (II) of clinical trials. Phase IV involves post-registration studies of drugs that have proven their effectiveness in relation to other pathologies (alzforum.org , April 2017).

In the search for new therapies for AD, beta-amyloid has become the most obvious target. Pharmaceutical companies have focused their efforts on creating a drug that can destroy existing plaques and/or prevent their formation. According to the website alzforum.org , of all antiamyloid drugs – those that should affect beta-amyloid and its precursor APP – 28 have reached clinical trials. And only 10 of them are participating in trials so far: the rest have already shown their ineffectiveness against Alzheimer's disease. Such a failure suggests that beta-amyloid is not such an indisputable target as it was previously thought. It is likely that approaches to therapy will be revised soon. Clinical trials of some drugs from this group will end in 2018, while most studies will be completed after 2020. But even with clinical effectiveness, new drugs will reach the consumer even later. At the same time, there remains a high probability that the studied drugs will not show the necessary effectiveness, and this will be the most serious blow to the amyloid hypothesis. In this case, it turns out that years of labor and billions of dollars have been wasted chasing a ghost.

Active and passive immunotherapy has become one of the ways to combat beta-amyloid. Active immunotherapy is vaccination with a substance, in response to the introduction of which the patient's body produces antibodies that bind extracellular amyloid deposits and destroy them with the help of immune reactions. The first of the drugs for active immunization was AN-1792, an artificially synthesized and modified β-amyloid. During preliminary studies, the drug showed the ability to reduce the number of amyloid plaques. However, when the work continued, it turned out that vaccination with AN-1792 led to a decrease in the volume of the brain as a whole and an increase in the ventricles. The volume of the hippocampus also decreased. Of course, the drug trials were stopped [25]. Studies of other means for active immunization against beta-amyloid have also failed. Currently, the drug AADvac1 is being tested for active immunization against tau protein. In the first phase of clinical trials, it has shown its safety and ability to induce an immune response in patients [26].

Passive immunotherapy involves the introduction of ready-made antibodies. The use of human immunoglobulin in Alzheimer's disease did not give significant positive results, so scientists switched to specific anti-amyloid antibodies. A monoclonal antibody called crenezumab is currently undergoing phase II and III clinical trials overseen by Hoffmann – La Roche. The drug is being tested on patients with pre-dement changes in cognitive functions (mild cognitive impairment, MCI). This approach is justified by the low effectiveness of drugs with a detailed picture of the disease. The earlier treatment begins, the greater the result can be achieved.

It is possible to influence amyloid not by its destruction in already formed plaques, but by preventing the formation of amyloid deposits. Inhibitors and modulators of β- and γ-secretases are targeted at this stage of the pathogenesis of AD (Fig. 9) [27].

Figure 9. Processing scheme of β-amyloid precursor protein (APP). The transmembrane protein APP is cut into two parts using enzymes. First, the β-secretase works, then the γ-secretase is connected, which cuts out the β-amyloid from the transmembrane protein [27].

A molecule called JNJ-54861911, which suppresses the activity of β-secretase, is currently being tested by Janssen and Shionogi Pharma. Its use has proven to be safe for different groups of elderly patients, and phase III of large clinical trials of the drug has now been launched. From 2017 to 2023, more than one and a half thousand patients with the initial manifestations of Alzheimer's disease will participate in this project. If the medicine shows its effectiveness, then it will appear on the market in a few more years. The researchers' concerns are caused by possible side effects. It is already known that the use of β-secretase inhibitors can impair synaptic plasticity [28] and cause depigmentation in laboratory animals [29].

There are also setbacks along the way. In mid-February 2017, Merck & Co. she reported the interruption of a clinical trial of verubecestat, another β–secretase inhibitor [30], [31]. It did not demonstrate sufficient effectiveness in phase III.

In the search for new drugs and approaches, the example of Axovant is interesting. The Axovant team has two scientists involved in the development of donepezil and memantine; the company is conducting research on several drugs against Alzheimer's disease and dementia with Levi's corpuscles. For the treatment of these disorders, Axovant offers the drug intepirdin, an antagonist of a certain class of serotonin receptors of the central nervous system, blocking of which leads to an improvement in cholinergic transmission. In the company's research, intepirdin is prescribed together with donepezil, that is, we are not yet a means for monotherapy of the disorder, but an adjuvant – a substance that improves the effect of the main drug. An example of such an adjuvant can be considered recently approved for the therapy of Parkinson's disease safinamide (Xadago, Newron Pharmaceuticals). In October 2016, Axovant began an annual clinical trial of intepirdine on 40 patients. Of course, the company plans to investigate monotherapy of dementia with intepirdin, but it will still remain an effect on the acetylcholine system of the brain, that is, only symptomatic treatment.

Inflammatory changes in brain tissues are often indicated as one of the links in the pathogenesis of Alzheimer's disease. Conventional anti-inflammatory drugs (ibuprofen, celicoxib and prednisone) have not shown activity against AD, but scientists are still searching in this direction. For example, the drug ALZT-OP1, which is a combination of cromoline and ibuprofen, is currently being tested. The drug is undergoing phase III clinical trials, and results are expected after 2018. In part, the impact on the inflammatory component of pathogenesis is associated with the hopes placed on the trials of pioglitazone, a drug used in type 2 diabetes mellitus. The TOMMORROW study evaluates the ability of pioglitazone to slow down the transition of Alzheimer's disease from the stage of mild cognitive impairment to the stage of dementia.

Again, this approach to the treatment of Alzheimer's disease now seems to be the most adequate, since there is no effective drug for the treatment of advanced stages of the disease. If we can't put out the fire, then let's at least try to hide the matches, scientists suggest. As we already know, changes in the brain in Alzheimer's disease begin several years before the manifestation of symptoms, and the effect of drugs at these early stages will delay the manifestations of the disease. The number of patients will gradually decrease. This will reduce the burden of BA on the healthcare system of any country until an effective cure is found. In addition, it is very important to develop screening methods that allow you to quickly and reliably determine the initial stages of cognitive impairment in Alzheimer's disease (and ideally without waiting for them).

Despite the ongoing search for drugs for Alzheimer's disease, the situation with her treatment does not look encouraging. The population of developed countries is rapidly aging and wants to live longer, while the health care system is not ready for an increase in the number of patients with dementia, whose care requires increasing costs. Despite the impressive amount of effort spent and grant injections into research, almost all new drugs turn out to be ineffective. Several drugs that are still approved for clinical use treat only symptoms, and even then at a short distance.

Obviously, the main reason for the failures lies in the lack of a reliable disease model for reliable drug testing. If a few decades ago scientists saw the root of the problem in the accumulation of aggregates of the "wrong" protein, which they will be able to quickly sort out, now they are inclined to believe that the causes of the disease lie much deeper – in the disruption of neurons and their relationship with the glia. And then another obstacle comes to the fore: we still don't understand well enough how the brain works and how its components interact. To understand Alzheimer's disease, scientists may have to return to more fundamental questions of neurobiology and study in more detail the changes that occur in the brain during aging. Solving these fundamental problems will give us hope for the emergence of effective drugs for the treatment of AD and other pathologies of the central nervous system.

Conclusion

The treatment slowed down the progression of the disease in Ekaterina Pavlovna for several months. But then the disease took its toll. Despite the expensive therapy, Ekaterina Pavlovna gradually lost her memory. Over time, she started calling her daughter friend, sister, and then mom. The son, who appeared rarely, was completely erased from the memory of Ekaterina Pavlovna, like all grandchildren. The daughter had to leave work to take care of her mother. There was no trace of the joyful and hospitable elderly woman. Ekaterina Pavlovna's world has narrowed down to an apartment in a high-rise residential area on the outskirts of the city.

One day Ekaterina Pavlovna ran away from home, and the family searched for her for half a day. The woman was found at the post office, where she came at nine in the evening for a pension. Since then, it has been locked up. When her daughter left the house, Ekaterina Pavlovna knocked on the door and shouted to be let out. Elena was crying in the entrance, but she had to go for food and medicines.

...A year and a half has passed. Ekaterina Pavlovna was already wearing diapers and could not get into the bath herself. She hardly spoke anymore and only walked endlessly from room to room, irritating Elena. Six months later, Ekaterina Pavlovna moved around the apartment with great difficulty, and then stopped getting up at all. The daughter fed her with a spoon, treated bedsores. One day Ekaterina Pavlovna suddenly had a fever and a cough. A week later, she died of pneumonia in her bed, repeating the path of thousands of old people all over the planet.

The average life expectancy of a person with verified Alzheimer's disease is 4-8 years after diagnosis. The patient's life expectancy directly depends on the quality of care for him. Dementia itself becomes the cause of death only in the terminal stages of the disease: the work of the brain is disrupted so much that it ceases to cope with the maintenance of vital functions. In the United States, between 2000 and 2014, mortality from Alzheimer's disease increased by 89%, while mortality from "standard" causes such as heart disease decreased. Indirectly, this indicates that the care of patients with dementia has improved. Whether this is good or bad is another question.

In other cases, infectious diseases become the cause of death: pneumonia, ascending infection of the urinary system, sepsis on the background of bedsores. Patients also die from concomitant pathology: cardiovascular and oncological diseases do not bypass those who are already ill with something.

The successes of modern medicine and the quality of care make it possible to prolong the life of elderly people, regardless of what diseases they suffer from. Despite the lack of significant progress in the treatment of Alzheimer's disease, we still have hope. This hope is fueled by research organized around the world and funded by many countries. Global and regional plans for the prevention and control of dementia have been developed. Scientists and doctors are trying to jointly resist the epidemic that is sneaking up on us. Thousands of specialists do not give up despite failures and continue to study the mechanisms of pathology development, potential ways of its therapy and early diagnosis.

There is hope for help from fundamental research of the nervous system. One of such programs is BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies). In the amount of more than $1.5 billion during 2017-2025, it will be funded by the US government as part of the 21st Century Medicine Act signed by the outgoing president in December 2016 (21st Century Cures Act). The program is designed so that by 2025 it should give a practical result for healthcare. Among the issues addressed by the BRAIN Initiative, there are studies of memory, in particular the work of the hippocampus – the area of the brain from which Alzheimer's disease begins. Thanks to the development of neuroscience, we are gradually beginning to understand how the brain works. Without this understanding, we will not find a solution to the global problem of Alzheimer's disease.

Anton Gopka, the founder of Atem Capital, acted as a consultant when writing this article.

Literature

1. L. E. Hebert, J. Weuve, P. A. Scherr, D. A. Evans. (2013). Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 80, 1778-1783;

2. Kenneth M. Langa, Eric B. Larson, Eileen M. Crimmins, Jessica D. Faul, Deborah A. Levine, et. al.. (2017). A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012. JAMA Intern Med. 177, 51;

3. Stephanie J. Soscia, James E. Kirby, Kevin J. Washicosky, Stephanie M. Tucker, Martin Ingelsson, et. al.. (2010). The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide. PLoS ONE. 5, e9505;

4. Biomolecule: Perhaps the beta-amyloid of Alzheimer's disease is part of innate immunity;

5. Todd E. Golde. (2016). Alzheimer disease: Host immune defence, amyloid-β peptide and Alzheimer disease. Nat Rev Neurol. 12, 433-434;

6. Biomolecule: β-amyloid: invisible enemy or secret protector? The Tangled Path of Alzheimer's Disease;

7. Murray Grossman. (2010). Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol. 6, 88-97;

8. K. A. Vossel, K. Zhang, J. Brodbeck, A. C. Daub, P. Sharma, et. al.. (2010). Tau Reduction Prevents A -Induced Defects in Axonal Transport. Science. 330, 198-198;

9. Erik S Musiek, David M Holtzman. (2015). Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci. 18, 800-806;

10. Biomolecule: Death after Life, Alzheimer's Disease and Why we Want Change;

11. Biomolecule: Alzheimer's Disease: The gene I'm crazy about;

12. Yu-Wen Alvin Huang, Bo Zhou, Marius Wernig, Thomas C. Südhof. (2017). ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion. Cell. 168, 427-441.e21;

13. Wahlund L.O., Westman E., van Westen D., Wallin A., Shams S., Cavallin L. et al. (2017). Imaging biomarkers of dementia: recommended visual rating scales with teaching cases. Insights Imaging. 8, 79–90;

14. Anne M. Fagan. (2014). CSF Biomarkers of Alzheimer’s Disease: Impact on Disease Concept, Diagnosis, and Clinical Trial Design. Advances in Geriatrics. 2014, 1-14;

15. Bob Olsson, Ronald Lautner, Ulf Andreasson, Annika Öhrfelt, Erik Portelius, et. al.. (2016). CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. The Lancet Neurology. 15, 673-684;

16. Biomolecule: A molecule of sound mind;

17. Francis P.T., Palmer A.M., Snape M., Wilcock G.K. (1999). The cholinergic hypothesis of Alzheimer's disease: a review of progress. J. Neurol. Neurosurg. Psychiatry. 66, 137–147;

18. Jacqueline Birks, Richard J Harvey. (2006) Donepezil for dementia due to Alzheimer's disease;

19. Jacqueline S Birks, John Grimley Evans. (2015) Rivastigmine for Alzheimer's disease;

20. Clement Loy, Lon Schneider. (2006) Galantamine for Alzheimer's disease and mild cognitive impairment;

21. Soysal P., Isik A.T., Stubbs B., Solmi M., Volpe M., Luchini C. et al. (2016). Acetylcholinesterase inhibitors are associated with weight loss in older people with dementia: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry. 87, 1368–1374;

22. Biomolecule: Very nervous excitement;

23. Rupert McShane, Almudena Areosa Sastre, Neda Minakaran. (2006) Memantine for dementia;

24. Taim Muayqil, Richard Camicioli. (2012). Systematic Review and Meta-Analysis of Combination Therapy with Cholinesterase Inhibitors and Memantine in Alzheimer’s Disease and Other Dementias. Dement Geriatr Cogn Disord Extra. 2, 546-572;

25. Yun Li, Yahong Liu, Zhaojun Wang, Yongjun Jiang. (2013). Clinical trials of amyloid-based immunotherapy for Alzheimer's disease: end of beginning or beginning of end?. Expert Opinion on Biological Therapy. 13, 1515-1522;

26. Petr Novak, Reinhold Schmidt, Eva Kontsekova, Norbert Zilka, Branislav Kovacech, et. al.. (2017). Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet Neurology. 16, 123-134;

27. Robert Vassar, Peer-Hendrik Kuhn, Christian Haass, Matthew E. Kennedy, Lawrence Rajendran, et. al.. (2014). Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J. Neurochem.. 130, 4-28;

28. Severin Filser, Saak V. Ovsepian, Mercè Masana, Lidia Blazquez‐Llorca, Anders Brandt Elvang, et. al.. (2015). Pharmacological Inhibition of BACE1 Impairs Synaptic Plasticity and Cognitive Functions. Biological Psychiatry. 77, 729-739;

29. Will next-gen BACE inhibitors dodge side effects? (2016). Kloster Seeon meeting on BACE proteases in health and disease;

30. Carroll J. (2017). Another Alzheimer's drug flops in pivotal clinical trial. Science News;

31. Biomolecule: β-amyloid: invisible enemy or secret protector? The tangled path of Alzheimer's disease.

Portal "Eternal youth" http://vechnayamolodost.ru  12.05.2017