From Alois Alzheimer's (1906) to drug candidates (2013)

Alzheimer's disease: promising treatment methods

Svetlana Shchegol, "Weekly Pharmacy" www.apteka.uaMemory – the process of organizing and preserving past experiences – is of great importance in the life and work of every person.

Thanks to memory, we have an idea of previously perceived things or phenomena, as a result of which the content of consciousness is not limited to sensations and perceptions, but also includes the experience and knowledge acquired in the past. Sergey Rubinstein, a psychologist and philosopher, one of the founders of the activity approach in psychology, noted that without memory there would be neither knowledge based on past experience nor skills. There would be no psychic life closing in on the unity of personal consciousness, and the fact of continuous learning passing through all life and making us who we are would be impossible.
Memory loss (dementia) has various causes and may indicate diseases in which cognitive function is degraded. The most common is dementia in Alzheimer's disease (Jorm A.F. et al., 1987).

Alzheimer's disease is a neurodegenerative disease first described in 1906 by the German psychiatrist Alois Alzheimer.

The decrease in mental abilities in this pathology is manifested primarily in the form of memory impairment. This is followed by disturbances in the emotional sphere and a state of depression is noted.

Despite the fact that Alzheimer's disease mainly develops as the body ages, the disease itself is not a natural result of aging.

The gradual decrease in the functional activity of the brain, which is accompanied by this disease, is due to two main damage to the nervous system: nerve cells transform into neurofibrillary tangles; protein globules accumulate in the brain.

Alzheimer's disease most often develops in people over the age of 65 (Bermejo-Pareja F. et al., 2008). However, its early form is very rare. According to the annual report of the International Association for the Fight against Alzheimer's Disease (The World Alzheimer's Report, 2010), the number of patients with this pathology in the world increased from 24 million in 2001 to 35.5 million in 2010.

Possible etiology of Alzheimer's diseasePossible causes of the disease are outlined in 3 main hypotheses.

According to the first of them – cholinergic – Alzheimer's disease is a consequence of impaired synthesis of the neurotransmitter acetylcholine (Davies P., Maloney A., 1976; Wenk G., 2003). In 1991, the amyloid hypothesis was proposed, whose followers believe that the underlying cause of this pathology is the accumulation of beta-amyloid protein fragments in the brain (Hardy J., Allsop D., 1991; Mudher A., Lovestone S., 2002). Proponents of the tau hypothesis believe that abnormal (hyperphosphorylated) tau protein triggers a biochemical cascade leading to the development of the disease, due to impaired function of neurofibrils in the neuron body with disintegration and collapse of the microtubular transport system of the neuron (Mudher A., Lovestone S., 2002).

Today, Alzheimer's disease is identified as proteinopathy caused by the accumulation of abnormal proteins – beta-amyloid and tau protein in brain tissues, which leads to degeneration of neurons.

Symptoms and diagnosis of the diseaseSymptoms of Alzheimer's disease manifest in all patients in different ways.

However, it is possible to identify common features of this pathology. First of all, memory and attention decrease in patients with Alzheimer's disease, there is a violation of thinking and learning, patients are disoriented in time and space, have difficulty in choosing words. Due to the steady progression of dementia, patients lose the ability to perform certain actions.

There are 4 stages in the progression of Alzheimer's disease. The symptoms of the first – premementia – are sometimes confused with the manifestation of aging or a reaction to stressful situations. It becomes difficult for patients to recall recent events and assimilate new information. They lose the ability to plan and focus on anything, and apathy also appears, which persists throughout the disease.

The second stage is early dementia. It is manifested by agnosia, a condition in which visual, auditory or tactile perception is disrupted while maintaining sensitivity and consciousness. In some patients, already at this stage, violations of speech and motor functions begin, there is a gradual impoverishment of vocabulary, reduced fluency of speech, the ability to express thoughts in writing. But a person still quite adequately operates with simple concepts and terms when speaking.

At the third stage of Alzheimer's disease, which is called moderate dementia, the patient's condition worsens significantly. People are increasingly choosing the wrong words to replace the forgotten ones, because their vocabulary is scarce and not replenished. The loss of reading and writing skills begins, coordination of movements is disrupted. It is difficult for the patient to cope with most everyday tasks, sometimes he does not recognize relatives and family members. Many patients develop irritability, sudden crying or laughing, spontaneous aggression, hallucinations, resistance to help or care. Urinary incontinence is possible.

The fourth stage of Alzheimer's disease is severe dementia. The patient is completely dependent on outside help. Speech mastery is reduced to individual phrases or words, and eventually speech is completely lost. The patient's condition is exhausted and apathetic, although sometimes there are attacks of aggression. A person eats very little, loses muscle mass, practically stops moving, and then cannot get out of bed on his own at all. Death does not occur from Alzheimer's disease, but from side factors (for example, bedsore ulcers or pneumonia).

There is no universal method for diagnosing the disease, except for a brain biopsy, which is carried out in rare cases, because it is a very dangerous procedure. The crucial importance is given to differential diagnosis with other diseases that cause dementia. Exclude malignant neoplasms, injuries, infectious diseases, metabolic disorders, drug overdose, depression, anxiety syndromes. In order to distinguish Alzheimer's disease from other diseases and varieties of dementia, such medical imaging methods are used: computed tomography, magnetic resonance imaging, photon emission computed tomography or positron emission tomography (National Institute for Health and Clinical Excellence, 2006).

Pathogenetic therapy of Alzheimer's diseaseThere are several main directions of pharmaceutical therapy of this pathology, the most developed of them are:

1) compensatory (substitution) – aimed at overcoming neurotransmitter deficiency in various neuronal systems that affect the development of Alzheimer's disease to a greater or lesser extent; 2) neuroprotective – helps to increase the viability of neurons and neuronal plasticity; 3) vasoactive; 4) anti-inflammatory; 5) hormonal.

Today it is impossible to completely cure Alzheimer's disease. However, modern methods of therapy can slow down the development of degenerative changes in the cells of the cerebral cortex. For this purpose, pharmacotherapy is used, as well as methods of psychosocial influence.

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have now approved 4 drugs for the treatment of cognitive impairment in Alzheimer's disease – 3 acetylcholinesterase inhibitors and memantine, an NMDA–glutamate receptor antagonist.

In 2007, a working group of the European Federation of Neurological Societies (EFNS) developed recommendations for the diagnosis and treatment of Alzheimer's disease and other types of dementia. These EFNS guidelines are based on the results of scientific reports, meta-analyses, systematic reviews, as well as clinical experience (Waldemar G. et al., 2007). According to EFNS researchers, cholinesterase inhibitors are the most effective in the treatment of Alzheimer's disease in the early stages. They inhibit enzymes that destroy acetylcholine in the synaptic cleft (the space between the membranes of the pre- and postsynaptic cell through which the mediator must diffuse). Thanks to acetylcholinesterase inhibitors, the neurotransmitter acetylcholine can act longer in the synaptic cleft. The lack of acetylcholine caused by Alzheimer's disease is partially compensated. According to the mechanism of action, there are 2 classes of cholinesterase inhibitors: class I – acetylcholinesterase inhibitors, class II – acetylcholinesterase and butyrylcholinesterase inhibitors.

For the treatment of Alzheimer's disease in the late stages, memantine is used, which is a non-competitive antagonist of NMDA-glutamate receptors, slows down glutamatergic neurotransmission and the progression of neurodegenerative processes, has a neuromodulating effect, helps normalize mental activity, improves memory, increases the ability to concentrate attention, correction of motor disorders (US National Library of Medicine, 2004).

Both acetylcholinergic drugs and memantine contribute to the regression of the main symptoms of dementia: cognitive, behavioral, psychotic and functional disorders.

Acetylcholinesterase inhibitors and memantine act on different pharmacological targets and do not show drug interaction, so they can be used simultaneously. In case of insufficient effectiveness of monotherapy, combination therapy is most appropriate.

Promising methods of treatmentTo date, there is no definitively confirmed treatment method that would help prevent or significantly slow down the progression of Alzheimer's disease.

Since the existing therapy for this pathology does not give the desired results, researchers around the world are developing new methods of treatment. Fundamental research is gradually revealing some links in the pathogenesis of dementia (especially in Alzheimer's disease) in order to create a theoretical basis for the development of new therapies.

Clinical studies of Alzheimer's disease are aimed at correcting basic pathological changes in patients. One of the typical targets for drugs undergoing research are accumulations of beta-amyloid, which need to be reduced. Immunotherapy directed against beta-amyloid protein is a possible way to slow down the development of Alzheimer's disease. Unlike the usual vaccination carried out in advance, in the case of this disease, the vaccine is administered after diagnosis. According to the researchers' concept, the patient's immune system should recognize and attack amyloid deposits, reducing their size and facilitating the course of the disease (Hawkes C., McLaurin J., 2007; Solomon B., 2007; Woodhouse A., Dickson T., Vickers J., 2007).

The first vaccine against Alzheimer's disease – CAD106 – was developed by specialists of the Karolinska Institute (Karolinska Institute, Sweden). The mechanism of action of the vaccine is to produce antibodies to beta-amyloid without activating a specific type of T-cells. The vaccine has passed a phase I clinical trial. Its results suggest that it has a favorable safety profile and causes an acceptable immune response in patients with Alzheimer's disease. More extensive studies are needed to confirm the safety and evaluate the effectiveness of the CAD106 vaccine (Winblad B., Andreasen N., Minthon L., et al., 2012).

Another candidate for drugs for the treatment of Alzheimer's disease is MDA7. In the course of studies conducted by scientists of the Lerner Research Institute at the Cleveland Clinic (Cleveland Clinic's Lerner Research Institute) and the Institute of Anesthesiology (Anesthesiology Institute), MDA7, which was developed for the treatment of neuropathic pain syndrome, demonstrated potential in Alzheimer's disease. According to the results of studies published in The Neurobiology of Aging, MDA7 causes an immune response that slows down the process of developing Alzheimer's type dementia. Mohamed Naguib, professor of anesthesiology at the Cleveland Clinic's Lerner College of Medicine, said that in an animal experiment, MDA7 helped restore the process of cognition, memory and synoptic plasticity. It is known that inflammation is an important factor in the development of Alzheimer's disease. MDA7 has anti-inflammatory properties and affects the CB2 receptor (one of the two cannabinoid receptors in the human body). At the same time, MDA7 does not exhibit the side effects inherent in cannabinoid drugs.

Another potential drug that can be used for Alzheimer's disease is considered a drug for the treatment of diabetes mellitus. According to Medical Xpress, the corresponding study was conducted by a group of specialists led by Kelly Dineley from The University of Texas Medical School (The University of Texas Medical Branch) on animals. The hereditary information of the animals has been genetically modified to mimic the symptoms of Alzheimer's disease, in particular cognitive impairment. Due to changes in the genome of animals, there was an increased activity of enzymes from the group of classical mitogen-activated protein kinases (MAPK), which provide synaptic signal transmission between neurons. As a result of a violation of the function of these enzymes, memory and learning ability decrease. Researchers injected animals with rosiglitazone, a drug from the group of thiazolidinediones, which is used in the treatment of insulin–dependent diabetes mellitus. The drug acts on receptors activated by peroxisomal proliferators. Receptors regulate the work of genes, as a result of which the activity of MAPK is normalized. The results of the study showed that after administration of the drug, memory and learning ability improved in animals.

The search for effective drugs for the treatment of senile dementia of the Alzheimer's type is also being carried out in Southwest Asia. Researchers from Sultan Qaboos University in Muscat (Sultan Qaboos University) came to the conclusion that the polyphenols present in dates that grow in their country can help in the fight against Alzheimer's disease. In laboratory conditions, experts have found that each variety of dates affects the slowing of fibrillation of beta-amyloid protein with a strength of 5% to 99%. A strategy aimed at preventing or slowing down the fibrillation of the beta-amyloid protein can be used for the prevention and therapeutic treatment of senile dementia, according to scientists from Sultan Qaboos University. They plan to continue their research and hope that the results obtained will help in the development of new drugs for the prevention and treatment of Alzheimer's disease.

In 2013, research on the new drug MK-8931 will begin in the UK. It is assumed that taking it daily will help stop the development of Alzheimer's disease. The mechanism of action of this drug is the inhibition of the beta-secretase enzyme, which cleaves the beta–amyloid precursor protein into peptides. Thus, MK-8931 blocks a biochemical process known as the amyloid cascade. The results of studies conducted by MSD with the participation of 200 patients showed that MK-8931 reduces the concentration of beta-amyloid in the cerebrospinal fluid by almost 92%. It is planned to conduct a study with the participation of 1,700 patients. However, conclusions will be made only by 2016, since patients with early stages of Alzheimer's disease will participate in it.

We can't change our age or the structure of our genes. But a healthy lifestyle can reduce the risk of developing a number of diseases, including those that affect the brain and cognitive functions. By investigating lifestyle factors, experts are developing drugs that can activate protective biochemical mechanisms or reduce the likelihood of degradation of cognitive function of the brain. In a statement, the Alzheimer's Research Center (Nantz National Alzheimer Center) from the Neurological Institute in Houston said: "You can reduce your risk of developing Alzheimer's disease and other dementias if you eat right, exercise, stay mentally and socially active, and keep stress under control."

Portal "Eternal youth" http://vechnayamolodost.ru10.01.2013