From Alois Alzheimer's to the present day
Alzheimer's disease
We publish a translation of the text by neuroscientist Mark Mattson about Alzheimer's disease. Read the original on the Serious Science website.
Alzheimer's disease is a specific type of brain disease in which a patient has problems with short–term memory. For example, a patient may have difficulty remembering what he said even in a very short conversation, and often repeats what he already said a little earlier. With the development of the disease, problems arise with circadian rhythms, long-term memory, and aggression and anxiety may also manifest. Ultimately, Alzheimer's sufferers don't recognize even close family members well.
History of Alzheimer's disease research
A little more than a hundred years ago in There was a psychiatrist in Germany who observed one patient with memory loss. She was about 70 years old, and she began to have problems with short-term memory and anxiety. Later, he examined her brain under a microscope with a pathologist and noticed what today we call amyloid plaques – deposits of amyloid in the brain. That psychiatrist's name was Dr. Alois Alzheimer.
The brain of an elderly person is normal (above) and with pathology caused by Alzheimer's disease (below), indicating the differences. // commons.wikimedia.org
Stages of Alzheimer's disease
At the earliest stage of Alzheimer's disease, the loss of short-term memory has almost no effect on a person's daily life. Many people have similar memory problems with age, but they do not have Alzheimer's disease. Because of this, it is difficult to understand whether a particular person will develop Alzheimer's disease, since problems with short–term memory, especially in old age, are very common - this is called "moderate cognitive disorders". Most often, a person goes to a neurologist and undergoes cognitive ability testing, according to the results of which it is possible to understand whether he has symptoms of moderate cognitive disorders or not. He continues to take such tests (usually every year): There are a number of tests that are offered to patients to test memory and learning abilities. If the results get worse and worse for 3-4 years, it signals that a person develops dementia. While only short-term memory is affected, patients will be able to lead a normal life for several years, but over time the disease progresses, and they may need help, for example, when driving a car, because they may forget where or why they are going.
When moving to the intermediate stage, a person begins to have problems with reading: after some time, he can no longer read, because he is not able to keep track of the plot. He reads a sentence, and then three more, and by this time he already forgets the first one, which he read just a minute ago. Thus, it becomes difficult to feed his intellect, stimulate the brain.
At the intermediate stage, the patient functions normally at home: he can get dressed, brush his teeth, eat. But he needs constant care because his short-term memory is no longer working. He may also develop other health problems.
At the very late stages, the patient may forget who he is, although he is still able to recognize familiar faces. He sees your face and smiles, even at the very end of life. So some elements of long-term memory are preserved in the later stages of the disease.
The most common cause of death in Alzheimer's disease is bacterial pneumonia. Due to brain damage, patients have problems chewing food, and they can inhale pieces of food into the lungs, thereby causing a bacterial infection of the lungs. It usually takes no more than 10 years from the early manifestations of moderate cognitive disorders to death. Constant care is usually needed for 2-4 years.
What happens in the brain in Alzheimer's disease
In the brain, nerve cells die at the same time, but even before that, the connections between them, synapses, stop working correctly: they weaken and eventually disappear. If you look under a microscope at the brain of a person who had Alzheimer's disease, you will see that in some parts of the brain – for example, the hippocampus, which is very important for learning and remembering – many neurons have disappeared. You will see accumulations of amyloid proteins: they are usually produced in all of us, but in a normal brain of a person who does not have Alzheimer's disease – at least in young people for sure – amyloids are thrown out and do not accumulate in tissues. Before the death of nerve cells, another pathology is observed: there is another protein inside the nerve cells – tau protein, and it also accumulates and eventually disrupts the ability of nerve cells to function normally.
Amyloids and Alzheimer's disease
When a person has problems with short-term memory and goes to the doctor to test cognitive abilities and do neuroimaging, he is diagnosed with "possible Alzheimer's disease" if there are signs that meet several specific criteria. The reason for this is that approximately 20-25% of patients with such symptoms do not have amyloids in the brain: amyloid deposits were considered a defining characteristic of Alzheimer's disease from the very beginning, so these patients do not have Alzheimer's disease. Their nerve cells die in the same way, memory problems arise, but there are no amyloid deposits. We don't know what exactly causes the problems, but often the vessels in the brain are damaged.
There are people, for example, over ninety, whose brain was functioning perfectly at the time of death, but if you look at it under a microscope, we will see deposits of amyloid. Apparently, in some people, nerve cells are resistant to harm from amyloid deposits. We are very interested in such cases, and we are trying to understand how their nerve cells get along with so much amyloid in the brain. In my laboratory, we conduct experiments with therapeutic fasting on mice and watch how amyloid accumulates in their brains. We inject them with a mutant human gene that causes the early development of Alzheimer's disease.
Early development of hereditary Alzheimer's disease
In a very small percentage of cases of Alzheimer's disease – just under 5% – it is caused by genetic mutations. For those who inherited such a gene from their parents, early development of the disease is characteristic, often in 40-50 years. In some families, symptoms of Alzheimer's disease appear as early as 35 years old.
The symptoms of early Alzheimer's disease cannot be distinguished from ordinary Alzheimer's disease, which develops in 70-90 years. We do not know the causes of these more frequent, late cases of Alzheimer's disease, but we do know that many cases of inherited Alzheimer's disease, which develops unusually early, are caused by mutation of genes encoding the precursor protein beta-amyloid and the enzyme presenilin-1; amyloid production increases, which is more prone to accumulation in the brain.
Aging and other factors
In the process of aging, two problems arise with the tissues of our body. Firstly, neurons cannot produce enough energy to maintain their work. In a nerve cell there is an organelle called "mitochondria": it produces energy. Very early, even before patients begin to have problems with learning and memory, we can detect a reduced level of energy in nerve cells. In the normal aging process, to some extent, this also happens.
Secondly, the production and accumulation of amyloid provokes oxidative stress, that is, the occurrence of free radicals that damage various molecules in the cell, including proteins, and membranes. In my laboratory, we worked a lot on how exactly free radicals push neurons to dysfunction and degeneration in Alzheimer's disease.
Alzheimer's disease and lifestyle
As for the risks of developing Alzheimer's disease, the key factor is the "vegetable" lifestyle, when people are physically inactive, eat too much and do not support intellectual activity. It turns out that if we don't load our body and brain with exercises or intellectual activity, apparently, nerve cells in the brain become more susceptible to aging-related stress, to reduced energy levels.
We roughly understand why physical exercise and intellectual activity can protect against Alzheimer's disease. All these factors – physical, energy and mental stress – increase the production of proteins called "nerve growth factors". One of them is neurotrophic nerve growth factor, and there is a lot of evidence that it plays an important role in the brain's ability to learn and remember. Neurotrophic nerve growth factor can stimulate the formation of new synaptic connections. In addition, lifestyle positively affects at least the ability of the hippocampus to stimulate neurogenesis, that is, the production of new neurons from stem cells.
Moreover, it seems that aerobic exercises like running, swimming or cycling are especially beneficial for the brain compared to yoga or weightlifting, although yoga and meditation can reduce stress levels. Some studies show that in older people, physical exercise has improved memory and learning abilities. I know of studies where people in their 70s, even 80s were offered an aerobic exercise program or just stretching – the study was conducted for several months, and their cognitive abilities were tested before and after the experiment. Those who performed aerobic exercises had improved memory and learning abilities, whereas in the control group that only did stretching, this did not happen.
However, all these factors cannot completely protect you from Alzheimer's disease: they can only reduce the risks or delay the onset of the disease.
Current research
Thus, we are investigating therapeutic fasting. In our study, we work with people who have obesity, but not diabetes. They are about 55-70 years old, they are getting old. They have obesity and insulin resistance, which precedes diabetes. We divide them into two groups: the first group fasts two days a week, and the second does not. Two months after the start of the diet, we test their cognitive abilities and look at the activity of neural networks on MRI. Based on our animal studies, we assume that there will be a positive trend. Then we take cerebrospinal fluid from them and measure substances, the level of which, as we have shown, should increase in the brain during fasting. We also measure the amount of amyloid and tau proteins in this liquid.
As for animal research, we are working a lot on other treatment options. For example, there is a drug that can stimulate mitochondria, and preliminary data show that it works. It has long been used to treat obesity, and we think that perhaps in the future it could potentially strengthen mitochondria in nerve cells. In addition, we have shown in mice that exercise can increase the number of mitochondria in nerve cells. This is interesting because it is very similar to the processes taking place in muscle cells: they are strengthened due to physical exertion, and nerve cells are also strengthened due to physical exertion.
Further directions of research
There are some very important issues that we need to study better. First, we need to learn how to somehow determine whether a person will develop Alzheimer's disease while he is still 50 years old: by the time the symptoms of the disease begin to manifest, millions of nerve cells have already died. Undoubtedly, it is because of this that a cure has not yet been found: by the time the symptoms of the disease appear, it is already too late.
There is a lot of interest in the question of whether it is possible to put new nerve cells in the brain – either by transplanting stem cells, or by transplanting embryonic neurons that will grow and form new neural circuits. It turns out that there are more glial cells in the brain than nerve cells. Glial cells support the functioning of nerve cells: they can supply energy, produce nerve growth factors, and so on. Glial cells do not die in Alzheimer's disease. Perhaps in the future it will be possible to stimulate glial cells so that they form neurons, because, unlike nerve cells, glial cells can divide. Several laboratories have shown that it is possible to make stem cells from a patient's skin cells and add two or three genes to them so that they become neurons, or turn glial cells into neurons directly. So far, all this is done only in vitro, but there are technologies that will allow a person to introduce these genes that stimulate glial cells directly or indirectly so that they form neurons in the brain. Now this is done on animal models.
So, perhaps in the future it will be possible to replace the dead nerve cells. If we do this in the early stages of the disease, we can replace the cells that support short-term memory, and long-term memories will not be affected. Thus, a person will be able to form new memories again. This is not science fiction: judging by what we know, in theory it is possible. The only question is the creation of technologies and approaches that are necessary for the safe conduct of such operations in humans.
Portal "Eternal youth" http://vechnayamolodost.ru