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10J.J. Bakhronov, M.M. Kuddusov, M.N. Nigmatullaev, Sh.B. Jamoliddinov, R.N. Muhiddinzoda, D.A. Otakulov, S.S. Khakimov, D.G. Nizamova
PATHOGENESIS OF ALZHEIMER'S DISEASE
This review article provides the most relevant data of the epidemiology of Alzheimer's disease (AD) and an assessment of the magnitude of the economic damage, there are also mechanisms of the pathogenesis of this disease, which is based on the "amyloid cascade". In addition, special attention is paid to the clinical manifestations of AD and the corresponding symptomatic therapy.
Key words: Alzheimer's disease; amyloid cascade; cholinesterase inhibitors; antagonists of NMDA receptors; vitamin D.
Alzheimer's disease (AD) or dementia of the Alzheimer's type is the most common form of primary degenerative dementia, characterized by a gradual inconspicuous onset in the elderly or senile age, the steady progression of memory disorders and higher cortical functions up to the total collapse of the intellect and mental activity in general, as well as a characteristic complex neuropathological signs. The prevalence of AD is a rather urgent problem. According to statistics, there are about 50 million people in the world with dementia syndrome, of which about 60-70% of all cases are Alzheimer's disease. The percentage increases with age: 3% of all people aged 65-75 have the disease, 17% in the 75-84 age group, and more than 32% among people over 84 years of age. [1]
In addition, Alzheimer's disease, like all forms of dementia, has a serious social and economic impact on the life of not only the patient himself, but also his relatives and friends. In the later stages of the disease, the patient needs almost constant care, which will certainly affect the emotional and financial state of his environment. Thus, in 2015, the global cost of care and treatment for patients with dementia was estimated at 818 billion US dollars. [6]
Even today, the pathophysiology of Alzheimer's disease is not fully understood. According to the prevailing "amyloid cascade" hypothesis, accumulation of beta-amyloid is at the forefront of disease progression. Amyloid precursor protein (APP) is a type 1 transmembrane protein that is produced by several cell types. In the central nervous system, APP protein is cleaved in two different ways, in which the second step in both cases involves cleavage by y-secretase. In the non-amyloidogenic pathway, APP is first cleaved by a-secretase, resulting in a "secreted" extracellular product called sAPPa and a membrane-bound 83 amino acid C-terminal fragment (C83). Cleavage of C83 with y-secretase yields another secreted fragment (p3) and an amyloid intracellular domain (AICD). [1]
In the amyloidogenic pathway, the APP protein is cleaved by p-secretase (BACE-1), resulting in the secreted extracellular product sAPPp and the amino acid C99, which subsequently forms beta-amyloid Ap and AICD under the influence of y-secretase. The regulation of these pathways is not well understood, but it is hypothesized that it is the overproduction of normally water-soluble beta-amyloid that causes it to self-assemble into oligomers that form the amyloid plaques found in brain samples. Their accumulation leads to a gradual decrease in the patient's cognitive functions, and both plaques and beta-amyloid itself have toxic properties. The subsequent inflammation and oxidative processes lead to the death of cells and neurotransmitters (especially acetylcholine), which causes the symptoms of this disease.
At the moment, numerous studies conducted, on the one hand, could not unequivocally prove this hypothesis, but on the other hand, they expanded the knowledge base about the molecular genetic features of the disease and proposed new hypotheses about the pathophysiology of AD. Thus, according to another widespread hypothesis, the main role in the mechanism of the development of pathology may belong to the tau protein, which is one of the representatives of the group of proteins associated with microtubules. In a hyperphosphorylated state, it affects presynaptic and postsynaptic compartments, disrupting signaling pathways, mitochondrial function, and axonal transport, in which it also participates. Like amyloid beta, hyperphosphorylated tau can localize to dendritic spines early in the disease process and influence postsynaptic receptor signaling. Insoluble forms of tau protein also lead to microtubule structural damage (the main function) and their disorganization. [4]
© J.J. Bakhronov, M.M. Kuddusov, M.N. Nigmatullaev, Sh.B. Jamoliddinov, R.N. Muhiddinzoda, D.A. Otakulov, S.S. Khakimov, D.G. Nizamova, 2023.
Despite the fact that these hypotheses have long been considered as different points of view on the pathogenesis of the disease, today there are already research data indicating the influence of beta-amyloid on the formation of hyperphosphorylated forms of the tau protein, which implies the relevance of the development of joint anti-Aß and anti- -tau therapy.
Recently, the question of the importance of genetic predisposition and its influence on the course of the disease has been increasingly raised in the issue of AD pathomorphology. The first such identified gene associated with this disease was coding for the beta-amyloid precursor protein APP at loci 21q21.2-21q21.3. Approximately 25 different APP mutations have been found, and they are associated with about 15% of all cases of the hereditary form of Alzheimer's disease. Most cases (from 18 to 70%) are associated with a mutation in the 14q24.3 locus of the PSEN1 gene, which encodes the protein of the y-secretase component. An important role is also assigned to the gene encoding apolyprotein E (ApoE). ApoE, in addition to the transport of cholesterol in the CNS, is involved in metabolic processes, aggregation, and accumulation of Aß. This gene has three alleles: e2, e3 and e4, it is believed that the presence of e2 reduces the risk of AD, while the prevalence of e4 among patients with AD is much higher than in healthy people. AD risk factors also include a mutation at the 8p21-p12 loci of clusterin (CLU), another apolipoprotein involved in Aß metabolic processes.
Clinical manifestations are associated with neurological and psychiatric symptoms. There are three stages of Alzheimer's disease.
Early stage: often goes unnoticed as symptoms come on gradually. Common symptoms of this stage include forgetfulness, disorientation in a familiar area, loss of track of time.
Moderate stage: Alzheimer's disease progresses and with them the symptoms become more pronounced. A person's orientation at home is disturbed, there are difficulties in communication, the need for help in caring for himself, the first cases of forgetfulness that are noticeable to others.
Late stage: In the late stage of Alzheimer's disease, almost complete dependence and passivity develops. Memory impairment becomes significant, and physical signs and symptoms become more obvious. There is a complete loss of orientation in time and space, difficulty in recognizing loved ones and anxiety about this, difficulties in movement, behavioral changes, including bouts of aggressive behavior. [6]
To date, there is no complete pathogenetic or replacement therapy for Alzheimer's disease. Classical symptomatic therapy includes two types of drugs. The first and leading group are cholinesterase inhibitors. Typical members of this group used in the treatment of Alzheimer's disease are donepezil, rivastigmine and galantamine. These drugs are most effective in the early and middle stages of the disease; in severe cases, its effectiveness is markedly reduced. The choice of a particular drug depends on the combination of the greatest effectiveness and the least side effects. [1]
So far, only one clinically proven and approved substance, memantine, belongs to the second group of substances. It belongs to a class of drugs called NMDA receptor antagonists, the principle of its action is associated with the modulation of glutamatergic transmission, providing cortico-cortical and cortico-subcortical connections in the GM. Its effect is to improve and stabilize cognitive functions, reduce behavioral disorders in patients with Alzheimer's disease at all stages (especially at the stage of moderate and severe dementia).
Huperzine A, another as yet unapproved NMDA antagonist, is also being studied. It is derived from herbs in the Barantsev family. Studies have found that large doses of Huperzine A cause improvements in mental alertness and activity in daily life. [2]
There are also groups of drugs, the use of which is associated with the treatment of individual symptoms in Alzheimer's disease. For example, selective serotonin reuptake inhibitors (SSRIs), as well as some tricyclic anti-depressants, are used to improve sleep, mood, and behavior. Escitalopram, one of the representatives of SSRIs, is recommended as a first-line drug for depressive conditions, however, in some cases, trazodone or mirtazapine, which, among other things, have a pronounced sedative effect, should be prescribed to simultaneously eliminate sleep problems and mood swings. Neuroleptics and antipsychotics try not to use. Among benzodiazepines, clonazepam is used as an exception for REM sleep disorders. [1]
To date, vitamin D deficiency has been recognized as one risk factor for developing any form of dementia, so patients with dementia or a genetic predisposition to it should take vitamin supplements. The effect of omega-3 fatty acids on cognitive improvement is also the focus of current research. [6]
With the existing symptomatic therapy, of course, the issue of curing the patient is not solved. The effect of these drugs only relieves acute symptoms and reduces the rate of development of pathology. Therefore, today, studies of future methods of treating AD are aimed at creating a full-fledged etiopathogenetic therapy: regulation of the formation of neurofibrillary tangles (tau protein) and beta-amyloid oligomers. Another approach in the treatment and prevention of AD is to strengthen transcortical networks and improve interneuronal connections to restore and maintain cognitive functions. In addition, early identification of patients from risk groups contributes to successful treatment, therefore, at present, part of the research is aimed at studying asymptomatic patients with
a genetic predisposition and at finding new biomarkers that indicate a high risk of developing dementia, including Alzheimer's disease.
Conclusion. Since the disease is based on a progressive neurodegenerative process, the prognosis of the disease is extremely unfavorable. When providing long-term adequate pathogenetic and symptomatic therapy, it is possible to slow down the progression of dementia or even stabilize it for a limited period within 3 years, depending on the stage of the disease and the timeliness of the start of therapy.
Bibliography:
1. Soria Lopez, J. A., González, H. M., & Léger, G. C. (2019). Alzheimer's disease. Geriatric Neurology, 231-255. doi:10.1016/b978-0-12-804766-8.00013-3
2. Weller J, Budson A. Current understanding of Alzheimer's disease diagnosis and treatment. F1000Res. 2018;7:F1000 Faculty Rev-1161. Published 2018 Jul 31. doi:10.12688/f1000research.14506.1
3. Busche, M. A., & Hyman, B. T. (2020). Synergy between amyloid-P and tau in Alzheimer's disease. Nature Neuroscience. doi:10.1038/s41593-020-0687-6
4. Meek PD, McKeithan K, Schumock GT. Economic considerations in Alzheimer's disease. Pharmacotherapy. 1998 Mar-Apr;18(2 Pt 2):68-73; discussion 79-82. PMID: 9543467.
5.World Health Organization. https://www.who.int/ru/news-room/fact-sheets/detail/dementia - date of access: 01/11/2021.van Marum RJ. Update on the use of memantine in Alzheimer's disease. Neuropsychiatr Dis Treat. 2009;5:237-247.doi:10.2147/ndt. s4048
BAKHRONOV JAKHONGIR JASUROVICH - student of the 521st group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
KUDDUSOVMUSLIMBEK MUHSIN UGLI - student of the 522th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
NIGMATULLAEV MUHAMMADJON NURALIYEVICH - student of the 522st group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
JAMOLIDDINOVSHERALIBAXTIYOR UGLI - student of the 507th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
MUHIDDINZODA RUKHSHONABONUNUMONKIZI - student of the 221st group of the medical faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
OTAKULOVDOSTONBEK ABDURASHID UGLI - student of the 504th group of the medical faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
KHAKIMOVSAIDJON SODIKJON UGLI - student of the 507th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
NIZAMOVA DILSHODA GAYRATJONOVNA - student of the 507th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
