Portrait of a mysterious killer
What is Alzheimer's disease – an epidemic, the burden of old age or a property of life?
Polina Loseva, "The Attic"
It is often called the scourge of the XXI century. It is inevitable, inexorable and incurable. But among the many age-related and neurodegenerative diseases, why did she become the "scourge"? "The Attic" decided to give the floor to imaginary supporters of three different approaches to Alzheimer's disease – an alien anthropologist, a pedantic naturalist and a severe evolutionist - in the hope of understanding what fateful combination of circumstances made it our number one enemy and whether it is a disease in our usual understanding.
The cause of dementia can be a number of neurodegenerative diseases. Alzheimer's disease has a huge number of brothers and sisters, among them Parkinson's disease, prion diseases, as well as several dozen variants of dementia, paralysis and hereditary syndromes. There are also unique combinations, for example, the Western Pacific complex (Parkinsonism, dementia and amyotrophic lateral sclerosis), which, as the name suggests, occurs only on the western Pacific coast. And recently, a children's variant of neurodegeneration was discovered – the "nodding syndrome" in children and adolescents in Uganda. Nevertheless, 60% of dementia patients in the world and the steady increase in the number of victims is precisely Alzheimer's disease, and not its lesser–known "sisters".
Having studied the symptoms of this disease more closely, our alien anthropologist could joke that "Alzheimer's" inside a single patient is also spreading like an epidemic. First, the brain cells responsible for the processes of attention, thinking and memory become ill and die. Following this, three main symptoms of the disease develop: aphasia (incoherent speech), apraxia (loss of simple skills like gesticulation or brushing teeth) and agnosia (loss of the ability to recognize objects and people). A person gradually loses control of his body, and everything ends up with dysfunction of other organ systems: exhaustion, loss of muscle mass, heart failure. Starting with the brain, the disease gradually takes over the whole body.
And at the molecular level, the epidemiological metaphor of our alien would be close to reality. The "soldier" of Alzheimer's disease – beta-amyloid (Aß) is a molecular lump that is formed from proteins of the same type when they unwind, losing their original shape, and tightly stick together. Then the lumps of beta-amyloid cause other proteins to unwind, and the chain reaction spreads to the rest of the brain tissue. Accumulating in the intercellular substance of the nervous tissue and the walls of blood vessels, Aß forms amyloid plaques, which are the main sign of Alzheimer's disease. Plaques are toxic to neurons and destroy the contacts between them – this is how neurodegeneration begins.
Since proteins are to blame for everything, the disease can be transmitted between organisms. And there is evidence of that. In the middle of the last century, doctors came up with a therapy that stimulates the growth of people: they crushed the pituitary gland of the dead, extracted growth hormone from there and injected patients with stunted growth. The patients grew up as a result, but only many of them were subsequently diagnosed with Alzheimer's disease, and recently scientists confirmed that beta-amyloid from donor hormone samples was to blame.
However, this is hardly a reason to consider Alzheimer's disease seriously contagious, since close contact with the brain or even the patient's blood in everyday life is practically impossible. True, there is evidence that surgeons suffer from Alzheimer's more often than other doctors, but on a very small sample. There is also an observation that the spouses of Alzheimer's patients fall victim to this disease more often than average (six times!), but this is due more to stress (provoking cell aging and inflammation) due to caring for an infirm relative than to direct contact. So it is still impossible to classify Alzheimer's disease as an infectious disease.
Expert
Despite the close attention to Alzheimer's disease, our attempts to invent a pill against it have so far led to nothing. The pharmaceutical companies Roche (the second largest pharma by market capitalization in 2018), Merck (the fifth) and Pfizer (the largest) have already capitulated to the deadly enemy, and recently another biotech company from the top three - Biogen. What prevents us from defeating such a carefully studied enemy? A pedantic naturalist would say that the point is the diversity of our opponent.
Firstly, his attack is very difficult to predict. Only in recent years, scientists have counted at least a dozen risk factors associated with this disease: age, female sex (this can be linked to age – women live longer on average), family history, obesity, high blood pressure, brain injuries, Down syndrome, social passivity, and so on. This list would allow a naturalist to assume that there are several types of pathology in front of him, caused by different reasons, because it is problematic to see a direct connection between them.
Secondly, it is not easy to distinguish it from its brothers–in-arms - other types of neurodegeneration (most of which, by the way, are still incurable). In addition to amyloid plaques in Alzheimer's disease, tangles of another protein, tau, appear in the brain. Sometimes there are clusters of alpha-synuclein protein, called Levi's corpuscles (they usually accompany the development of Parkinson's disease). Combinations of different proteins that damage brain tissue, the areas of their deposition and the consequences for the body are very diverse. Alzheimer's and Parkinson's diseases sometimes occur simultaneously, beta-amyloid is often adjacent to Levi's corpuscles. In addition, calcium and iron can accumulate in the brain and lead to dystrophy, muscle weakness or paralysis. Even for the most diligent naturalist, it would be difficult to classify all these pathologies: we have a whole palette of neurodegenerative diseases that are extremely similar to each other, and their specific manifestations depend on the type of proteins and the focus of their deposition.
Thirdly, it is almost impossible to see this enemy in advance. In this, Alzheimer's disease is somewhat similar to cancer. By the time the first symptoms of dementia appear, the brain is usually already seriously damaged. In addition, reliable diagnostics using PET (positron emission tomography) is expensive. Therefore, as in the case of cancer, medicine is looking for biomarkers in the blood, allowing you to track down the enemy even before the start of the battle. Neurofilaments are offered as candidates (as signs of neurodegeneration) or a complex of 10 proteins (taking into account additional risks – age and genetics). However, while the accuracy of these analyses leaves much to be desired, and the variety of protein signs in Alzheimer's disease does not allow creating a universal test.
The Accuser
But the main problem is that, even when faced with the enemy face to face, we still do not understand where his heart is and where to shoot. Now we are fighting mainly with the symptoms of the disease. For example, you can add the neurotransmitter acetylcholine to the brain (which the defeated neurons stop secreting, and the body begins to lack it). This is how the only currently approved drugs against Alzheimer's disease work, but they only soften the course of the disease. Or you can destroy beta-amyloid directly. This was the basis for the approach of Biogen, which recently refused to participate in the pursuit of Alzheimer's disease: they injected antibodies to beta-amyloid into the patients' bodies in order to activate the immune response in this way. Another company that is still afloat, United Neuroscience, operates in a similar way: they vaccinate patients with an amyloid-like protein, again setting up the immune system against it in advance.
Of course, it would be much more effective to hit the cause of the disease. But in order to aim correctly, it is necessary to decide what we consider the cause.
The first way is to announce that we are dealing with a bacterial epidemic and start fighting those who make our cells secrete a destructive protein. It is known that beta-amyloid is cruel not only to its own cells, but also to foreign, bacterial ones. It blocks their defense mechanisms, making them vulnerable to immune attack. Here an alien anthropologist could rejoice - this is a direct hint at the infectious nature of the disease: people one by one become infected with a bacterium and in response to this their neurons produce beta–amyloid, which destroys the nervous tissue. However, it is still unclear who exactly provokes this epidemic. The Alzheimer's Germ Quest Foundation even announced an award for the head of the pathogen microbe, but so far it has not been awarded to anyone. Among the suspects are not only bacteria, but also, for example, the herpes virus. However, the microbe Porphyromonas gingivalis attracted the most attention. This bacterium is known to cause periodontitis (inflammation of the ligaments holding the teeth in the gum), and can probably enter the brain from the mouth. At least, it has been repeatedly found in the brains of patients with Alzheimer's disease. Therefore, Cortexyme is now launching clinical trials of an antimicrobial agent that destroys Porphyromonas gingivalis. At the same time, it is known that this bacterium lives in the mouth and in 25% of healthy people. Does this mean that the epidemic theory is wrong? Or should we admit that all these people are also at risk?
The second way is to work on yourself, eliminating the genetic predisposition to the disease. There are several known genetic variants associated with an increased risk of developing Alzheimer's. This may be a mutation in genes encoding proteins that produce beta-amyloid from a useful precursor. This may be a mutation in the gene of the precursor protein itself. Finally, the most well-known mutation that increases the risk of developing the disease is in the APOE gene. It encodes a cholesterol transporter protein, and cholesterol holds the amyloid precursor protein in the cell membrane. And now the Weill Cornell Medicine clinic in New York is developing a gene therapy that corrects the AOE gene.
The third way is to assume that the formation of broken proteins is an inevitable sign of aging of brain cells, it's not just that the disease develops to old age. But since safe ways to rejuvenate cells in vivo are still unknown to us, we have to test complex approaches. For example, Alcahest is testing proteins from blood plasma that supposedly rejuvenate the brain by stimulating the formation of new neurons. Currently, this is the only clinical trial involving the transfusion of young blood to old donors; in other cases, such experiments have been suspended.
Finally, we can assume that in each case the disease has its own cause, and then follow the path of the naturalist and treat each patient individually. This is the basis of the dementia control protocol developed by an American doctor and author of the book "Ageless Brain" (in the original – The end of Alzheimer's) By Dale Bredesen. He suggests dividing Alzheimer's cases into three groups: those caused by inflammation, dystrophy or stress. Each patient passes tests that allow classifying his type of dementia, so that he can then work with it in a targeted manner. It is claimed that with the help of his technique, it was possible to reverse neurodegeneration in hundreds of patients. However, the authors of the report themselves say that this is not yet a panacea, but only a basis for future controlled clinical trials.
Lawyer
The failures that pharmaceutical companies suffer one after another suggest that we have a wrong idea of the true face of our enemy. Unlike real epidemics – like HIV infection - Alzheimer's disease is caused not by intruders from outside, but by our own brain cells. But what if this time bomb plays some initially useful role in our body? What if beta-amyloid is deposited in the nervous tissue because someone needs it?
We don't like beta-amyloid because it kills nerve cells. But in some cases, killing cells is beneficial. For example, if these are old cells that cannot function normally and, conversely, secrete pro-inflammatory substances and harm the surrounding "healthy" cells. In this case, beta-amyloid may be part of the cellular competition mechanism by which young and healthy cells survive old and diseased tissue. Based on this, we can imagine that without the death of nerve cells, the brain will work worse. Recently, scientists from Portugal turned off the proteins in the neurons of flies responsible for the death of the cells that lost in the competition, and neurodegeneration increased at the same time: aging cells dragged everyone else with them "to the grave". Based on this experiment, scientists have suggested that a person cannot be completely deprived of beta-amyloid without harm to health.
The track record of beta-amyloid does not end there. It is known that it can work as an antioxidant, neutralizing toxic free radicals in cells, and stimulate the division of neurons. Even tumor cells refuse to multiply if the ARP gene is turned off in them. This is probably why Alzheimer's disease is poorly compatible with cancer, and they rarely attack the same organism.
A severe evolutionist would suggest that we look at the situation from the other side. Alzheimer's disease fits into the same maxim as many other age–related pathologies: "a little is pretty." As soon as the physiological process that is beneficial to the body goes beyond its measured limits, it quickly turns into a merciless killer. Similarly, the theory of hyperfunction explains most age-related diseases. Excessive cell division gives a tumor, excessive blood clotting causes thrombosis, and paranoid protection from bacteria and toxins, i.e. the formation of beta-amyloid, causes Alzheimer's disease. At the heart of each of these diseases is a vicious circle. Cells secrete beta-amyloid as a defense against stress, bacteria or old cells – plaques form – cells die – survivors experience stress – and secrete beta-amyloid (or age). In this sense, Alzheimer's disease is a typical age–related disease: it has many origins (stress and aging of cells can occur for many reasons) and once you get into this rut, it is impossible to jump out of it.
Having listened to the evolutionist, modern gerontologists are trying to fight "Alzheimer's" in the same way as with other age-related diseases. Their common trouble is that they are based on physiological mechanisms that are useful for the same organism in youth, so it is impossible to cancel their action. The same variation of the AOE gene that increases the risk of developing the disease, at the same time enhances both fertility and cognitive abilities of the young organism. Therefore, gerontologists offer prevention – the same ways in which they expect to prolong the life of the body as a whole and slow down the aging of cells in particular. This is, for example, rapamycin – a drug that simulates partial starvation at the molecular level. Or quercetin is a substance of plant origin, which is being tested now as a senolytic, that is, a killer of old cells. Or just physical activity and diet are the key to a healthy lifestyle; however, while they help to avoid the accumulation of tau proteins in the brain only for animals, the data on humans are less unambiguous.
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The mistake of the alien anthropologist is that he confused cause and effect. Alzheimer's disease did not appear in response to microbial aggression. On the contrary, it came to the fore just after the efforts of doctors people got rid of other problems like accidental infections and poisoning. And the main risk factor for her remains age. In the USA, among people 65-74 years old, an average of 3% are sick (in Russia this percentage is slightly higher, at least in Moscow there are 4.5%), 75-84 years old – 17%, and over 85 years old – 32%.
Neurodegeneration develops according to the same laws as other age-related conditions, going through an evolutionary path from a saving mechanism to a deadly enemy. That is why our imaginary naturalist fails, mired in attempts to classify the types of dementia: Alzheimer's disease is not a disease in its pure form, but rather an immanent property of the system. A property of a living organism that has received an unaffordable longevity loan, which it is not able to cope with.
Meanwhile, the evolutionist suggests the following question: even if one day we unravel this ominous tangle and climb a little more on the ladder of longevity, what awaits us next, around the next corner?
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