Old age is not a joy

Tomsk scientists investigate the genetic basis of Alzheimer's disease

Olga Kolesova, "Search" No. 15-2017

Even in ancient Greece, doctors and philosophers associated old age with a weakening of the mind. I don't know if this prospect will please you, reader, but with an increase in life expectancy, having successfully passed the risk of oncological and cardiovascular diseases, we all get a chance to live up to the disease that bears the name of the German psychiatrist Alois Alzheimer - it was he who in 1907 first described a case of a disease associated with the gradual extinction of cognitive functions.

For more than a hundred years, doctors have failed to cope with a common disease of the central nervous system – 44 million people are ill in the world, 1.8 million officially diagnosed patients in Russia. When a person reaches the age of 65 every five years, the risk of getting sick increases exponentially, after 85, 20% suffer from this form of dementia. The existing theories of the occurrence of a terrible disease, in which a person gradually loses touch with the world and begins to lead a vegetative lifestyle, have not yet found unconditional confirmation. 

To date, three genes have been identified, mutations in which cause the presence of a rarer – early – form of Alzheimer's disease (it can begin from 40 to 60 years old, refers to monogenic, that is, hereditary, diseases). However, the genetic basis of the most common form – late–onset Alzheimer's disease – has not been definitively identified, besides, this disease is multifactorial, therefore, the presence of a mutation in the genes signals a certain degree of risk, but does not make the disease inevitable. You must agree, considering all the above, it is difficult to overestimate the importance of the project of the Russian Scientific Foundation "Genetic foundations of cognitive function variability in elderly people and in patients with Alzheimer's disease" carried out by the Tomsk National Research Medical Center of the Russian Academy of Sciences, the purpose of which is to compare the genetic component in normal and sick elderly people and find new genetic markers of the disease.

– We have a long–standing interest in this problem, - says the project manager, director of the Research Institute of Medical Genetics of the Tomsk NIMC Corresponding member of the Russian Academy of Sciences Vadim Stepanov. – The most common form of Alzheimer's disease – with a late onset – is a classic multifactorial, determined by the action of many genes, most of which are not yet known for sure. Some time ago, our institute carried out a study: about 60 partner genes were tested on the Russian population, whose contribution to the development of either Alzheimer's disease or schizophrenia was recorded in foreign genome-wide studies. In the course of this work, we found a significant intersection of the genetic bases of very different diseases from a medical point of view – Alzheimer's disease and schizophrenia. 

It is cognitive functions that are the area where the genetic mechanisms of these diseases intersect. Then a bolder hypothesis arose, of which there is not much evidence today: what if Alzheimer's disease and cognitive functions are normal – these are different stages of the same process? We want to understand how genetically inherited variability of cognitive functions appears in our population, as well as to find out exactly what the genetic component of Alzheimer's disease is. The most reasonable way to answer this question is to understand which genes determine cognitive functions in the elderly normally, and compare them with the genes of patients with Alzheimer's disease. To do this, we engaged the specialists of the Nebbiolo Clinical Research Center, who collected a huge sample of 2,000 people over 60 years old, characterized by a whole battery of modern neuropsychological tests, and adapted to Russian linguistic and cultural realities, creating an adequate tool for assessing cognitive functions in normal people. Our task is to find genetic markers, including new ones that have not been characterized before, which determine differences in individuals' thinking abilities.

– In America and Europe, the problem of Alzheimer's disease has been dealt with for a long time, which is associated with an increase in the average age of the population. When we started research seven years ago, we found out that there were only a few dozen officially diagnosed cases of late-onset Alzheimer's disease in Tomsk. Basically, patients were diagnosed with dementia, without differentiation by type," explains Oksana Makeeva, PhD, Director of the Nebbiolo Center for Clinical Research and Neuropsychological Testing. – Alzheimer's disease is also a form of dementia, but in order to reliably make this diagnosis, serious tools are needed, in particular neuropsychological tests. At that time, we were conducting joint research with Duke University (USA) on the study of cognitive functions in elderly people in the Russian and American populations and were preparing a project to study the possibility of postponing the age of onset of the disease with the help of drugs. Our research partner was Professor Allen Roses, the founding father of one of the leading centers for the study of Alzheimer's disease. It was Allen Roses who established in 1993 that the apolipoprotein E gene – more precisely, its APOE4 variant – is the leading genetic factor of late-onset Alzheimer's disease, which was repeatedly confirmed in the next 20 years. Later, Roses discovered another important gene located next to AOE, TOMM40. The professor's hypothesis was not immediately recognized, since beta-amyloid was considered the main "culprit" of the occurrence of the disease, contributing to the formation of pathological formations in the brain – amyloid plaques. A lot of pharmaceutical companies have spent a lot of money to find factors in amyloids that can be influenced to, if not stop, then at least slow down the development of Alzheimer's disease. Unfortunately, none of the drugs turned out to be effective enough to enter the market. Now scientists are inclined to believe that the amyloid theory hardly explains the main mechanism of triggering the disease. In this regard, genetic research is of particular importance.

Allen Roses was at the origin of our joint work – we trained neurologists and neuropsychologists and formed a team, Duke University specialists chose testing methods that helped assess different cognitive domains. The studies were conducted in parallel in Tomsk and in the USA to establish the features of neurocognitive functions in the Russian population. The main differences: in time tests, Russians attach more importance to the correct answers, rather than the speed of the test, for Americans, the factors of correctness and time are equivalent, which reflects the peculiarities of our cultures. Our study revealed a lot of undiagnosed diseases in elderly Russians, such as depression, heart disease or diabetes – all of them affect brain health and cognitive functions. But the main result of the project is that a sample of two thousand elderly people appeared in Tomsk, characterized by standard tests according to a standard methodology – so we got the purity of the phenotype, which is important for genetic research. In addition, we took blood for DNA from all the test subjects to study the influence of genetic factors on the performance of tests.

– Our project, supported by the RNF, is designed for 2016-2018, – comments Vadim Stepanov. – At the first stage, we tested already known genetic markers by comparing healthy people and patients with Alzheimer's disease. And, whatever verification methods we use, the cluster of genes located on the 19th chromosome comes to the fore - the already mentioned APOE, TOMM40 and others. We are working with the Montreal Cognitive Ability Assessment Scale (MoCA) test, the main indicator of which is the total score, in normal elderly people it varies from 15 to 30. At the second stage of the project, we will examine samples of 50 elderly people with the highest test score, 50 with the lowest, as well as a sample of patients with Alzheimer's disease, sequencing their exome (the most significant part of the genome that is responsible for protein coding) – we will conduct a comparative analysis to find common gene variants that determine variability of cognitive functions. Simply put, let's find out how different genes are in people with high and low cognitive parameters. If in 2016 we worked with dots in the genome – we analyzed about 70 genes, then in 2017 we will try to find the whole spectrum of genes related to the management of cognitive functions, identifying new genetic markers and trying to understand which genetic networks they are involved in. And in 2018, we will test the markers found on the entire population of 2000 people.

– When we find new genetic factors, it allows medicine to look for new methods of influencing the disease, – adds Oksana Makeeva. – It is interesting that some scientists have long considered Alzheimer's disease with a late onset as a process of natural aging of the body. There is a point of view that sooner or later everyone will have signs of this disease, it's just that many will not live to see it, having died from other causes. But Alzheimer's disease is not strictly a hereditary disease, here the genetic risk factor is very large, but it is not exhaustive. This gives us a chance, by adjusting environmental factors – lifestyle (regular intellectual load is very useful), nutrition, and thereby significantly postpone the onset of the disease. However, the question may arise as to how much information about genetic risk will be useful to a person today, in the absence of medicines. The whole complexity of the problem is illustrated by the story of a top manager of a large Uzbek company. A 50-year-old businesswoman, who is very responsible for her health, made a genetic passport, according to which she turned out to be a carrier of one APOE4 allele. The woman immediately went to South Korea for a more detailed examination, where amyloid plaques were found in her brain during a PET scan. Local doctors informed the lady that in 10 years she would be diagnosed with Alzheimer's disease. She turned to us to make sure of the accuracy of the diagnosis. We conducted a neuropsychological diagnosis and read her PET scan again - according to the tests, there were no signs of illness, only noted increased anxiety. The patient insisted on conducting a genetic test for monogenic forms – the test came back negative. During the genetic analysis, the genotype was also determined by the AOE – the patient turned out to be a carrier of the AOE3/3 genotype, that is, the most common of all possible genotypes. Not fully believing us, the business lady went to America. They confirmed our results there. That is, the whole story was built, firstly, on incorrect genotyping, and secondly, on an incorrect interpretation of the results. And a person has gone through all the circles of hell, not to mention the time and money spent. 

– This example clearly demonstrates how difficult it is to deal with genetic information, especially when a variant of clinical significance arises, – Vadim Anatolyevich believes. – Each of us is a carrier of many genetic mutations, among which there are about 10 lethal alleles (various forms of one gene that determine alternative variants of the development of a trait) in a "dormant" state. Which option is being implemented is unknown. In any case, what geneticists are doing now is directly related to personalized medicine, and not so much to treatment as to prevention and early diagnosis. And the search for genetic markers of Alzheimer's disease can be used in combination with cognitive tests for early personal prediction of the possible risk of developing the disease. I hope that in the future we will have joint research with pharmaceutical companies to lay the fundamental foundations not only for the diagnosis, but also for the treatment of the disease.

Portal "Eternal youth" http://vechnayamolodost.ru  17.04.2017