Alzheimer's disease
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Alzheimer's disease
The brain of an elderly person is normal (left) and with pathology caused by Alzheimer's disease (right), with an indication of differences.
ICD 10 G3030., F0000.
ICD 9 331.0331.0, 290.1290.1
OMIM 104300
DiseasesDB 490
MedlinePlus 000760
eMedicine neuro/13
MeSH D000544
Alzheimer's disease (also senile dementia of the Alzheimer's type) is the most common form of dementia, a neurodegenerative disease first described in 1907[1] by the German psychiatrist Alois Alzheimer.
As a rule, it is found in people over 65 years of age[2], but there is also early Alzheimer's disease — a rare form of the disease.
The global morbidity rate for 2006 was estimated at 26.6 million people, and by 2050 the number of patients may increase fourfold[3].
As a rule, the disease begins with subtle symptoms, but progresses over time.
Most often, short term memory disorder is recognized in the early stages, for example, the inability to recall recently memorized information.
With the development of the disease, there is a loss of long term memory[4], speech and cognitive functions are impaired, the patient loses the ability to navigate the situation and take care of himself.
The gradual loss of body functions leads to death[5].
When contacting a doctor and Alzheimer's disease is suspected, behavior is usually analyzed to clarify the diagnosis, a series of cognitive tests are performed, if possible, magnetic resonance imaging (MRI) is performed[6].
Individual prognosis is difficult due to variations in the duration of the disease, which can develop covertly for a long time, before symptoms become noticeable and a diagnosis is made.
The average life expectancy after diagnosis is about seven years[7], less than three percent of patients live more than fourteen years[8].
Currently, a complete understanding of the causes and course of Alzheimer's disease has not been achieved.
The key features of the disease are the accumulation of amyloid plaques and neurofibrillary tangles in brain tissues[9][10].
Modern methods of therapy only slightly mitigate the symptoms, but so far they do not allow either to stop or slow down the development of the disease.
Many promising therapies have reached the stage of clinical trials, the number of which in 2008 was more than five hundred, but it is unclear whether their effectiveness will be proven.
In 2013, the method of deep transcranial magnetic stimulation (Deep TMS) received the CE Mark approval for the treatment of symptoms of Alzheimer's disease along with other diseases[11][12].
Two American companies have stopped developing a once promising drug to alleviate the effects of memory loss in Alzheimer's disease after two clinical trials in which the drug failed to help patients.
The researchers reported that the positive dynamics of the disease in patients in the mild or early stage of Alzheimer's disease did not differ from that in the control group of patients who were given a placebo.
Pfizer and Johnson&Johnson said that all other research in this area has been discontinued.
Currently, there is no cure for Alzheimer's disease[13].
There are many ways to prevent Alzheimer's disease, but their impact on the course of the disease and its severity has not been noted.
Both to prevent and to combat the disease, it is often recommended to exercise, stimulate thinking and adhere to a balanced diet[14][15].
In 2016, there were reports that a drug created by Israeli scientists led to the complete disappearance of the symptoms of Alzheimer's disease in mice.[16]
Alzheimer's disease belongs to the diseases that impose the heaviest financial burden on society in developed countries[17][18].
Content
1 History 2 Epidemiology 3 Characteristics 3.1 Pre dementia 3.2 Early Dementia 3.3 Moderate Dementia 3.4 Severe Dementia
4 Causes 5 Pathophysiology 5.1 Neuropathology 5.2 Biochemistry 5.3 Pathological mechanism 5.4 Genetics
6 Diagnostics 6.1 Diagnostic criteria 6.2 Diagnostic methods
7 Disease prevention 8 Therapy and care 8.1 Pharmacotherapy 8.2 Psychosocial intervention 8.3 Care and supervision
9 Forecast 10 Culture and society 10.1 The burden on society 10.2 Patient care 10.3 Famous people, mass media, works of literature and cinema
11 Research directions 12 Notes 13 Literature 14 References
History[edit / edit wiki text]
Augusta Deter, Alois Alzheimer's patient, 1901
Doctors and philosophers of ancient Greece and Rome associated old age with a weakening of the mind[1], but it was only in 1901 that the German psychiatrist Alois Alzheimer noted a case of an illness that was later named after him.
Analysis of the disease of fifty year old Augusta D. he published it for the first time in 1907, after the patient he was watching died[19].
Over the next five years, eleven more similar descriptions appeared in the medical literature, and the authors of some of them already used the term "Alzheimer's disease" [1].
Emil Kraepelin was the first to call Alzheimer's disease an independent disease.
In 1910, he identified it as a subtype of senile dementia in the eighth edition of his textbook on psychiatry, giving it the parallel name "presenile dementia"[20].
For most of the twentieth century, the diagnosis of Alzheimer's disease was made only to relatively young patients who had the first symptoms of dementia at the age of 45 to 65 years.
The terminology changed after the 1977 conference on Alzheimer's disease, the participants of which came to the conclusion that the clinical and pathological manifestations of presenile and senile dementia are almost identical, although they did not exclude the existence of etiological differences[21].
Gradually, the diagnosis began to be made regardless of age[22], although for some time the term "senile dementia of the Alzheimer type" (SDAT) was still used to describe the disease in people over 65 years old, reserving the "classic" diagnosis of Alzheimer's disease for younger people.
As a result, the term "Alzheimer's disease" was formally adopted into the medical nomenclature as the name of a disease that is diagnosed regardless of age in the presence of appropriate symptoms that develop in a characteristic way and are accompanied by the appearance of typical neuropathological signs[23].
Epidemiology[edit / edit wiki text]
Life years adjusted for disability in Alzheimer's disease and other dementias per 100,000 population in 2004.
no data available ≤ 50 50-70 70-90 90-110 110-130 130-150 150-170 170-190 190-210 210-230 230-250 ≥ 250
Morbidity[24]
in persons over 65 years of age, the incidence of
(new cases)
per thousand
person years 65-69 3 70-74 6 75-79 9 80-84 23 85-89 40 90- 69
The two main indicators used in epidemiological studies are the incidence and prevalence of the disease.
The incidence rate reflects the number of new cases per unit of person time (usually the number of new cases per thousand person years), and the prevalence of the disease indicates the total number of people affected by the disease in the population at a particular time.
Cohort longitudinal studies (during which the initially healthy population is tracked for many years) indicate an incidence of 10-15 new cases per thousand person years for all types of dementia and 5-8 cases for Alzheimer's disease[24][25], which is approximately half of the total number of annual diagnoses.
Old age is the main risk factor, which is reflected in statistics: for every five years after the age of 65, the risk indicator increases approximately twice, growing from 3 cases in 65 years to 69 cases per thousand person years by 95 years[24][25], there are also gender differences — women are more likely to develop Alzheimer's disease, especially after 85 years[25][26].
The prevalence of the disease in the population depends on various factors, including morbidity and mortality.
Since the incidence increases with age, it is absolutely necessary to take into account the average age of the population in the study area.
In the United States, as of 2000, about 1.6 % of the population, both in general and in the 65-74 age group, had Alzheimer's disease.
In the group of 75-84 years, this indicator was already 19 %, and among citizens whose age exceeded 84 years, the prevalence of the disease was 42 %[27].
In less developed countries, the prevalence of the disease is lower[28].
According to WHO, in 2005, 0.379% of the world population suffered from dementia, and the forecast for 2015 reached a value of 0.441 % and an even larger percentage of the population, 0.556 %, may be affected by the disease by 2030[29].
The authors of other works come to similar conclusions[28].
Another study says that in 2006, the prevalence of the disease in the world was 0.40 % (a spread of 0.17-0.89 %, the absolute number is 26.6 million people, with a spread of 11.4-59.4 million) and predicts that the share indicator will triple, and the absolute number of patients will quadruple by 2050[3].
Characteristics[edit / edit wiki text]
The course of the disease is divided into four stages, with a progressive picture of cognitive and functional disorders.
Pre dementia[edit / edit wiki text]
The first symptoms are often confused with the manifestations of aging or a reaction to stress.
The earliest cognitive difficulties are detected in some people with detailed neurocognitive testing eight years before diagnosis[30].
These initial symptoms may affect the performance of not the most difficult everyday tasks[31].
The most noticeable memory disorder is manifested in difficulty when trying to recall recently learned facts and in the inability to assimilate new information[32][33].
Subtle problems of executive functions: concentration, planning, cognitive flexibility and abstract thinking, or a violation of semantic memory (memory of the meaning of words, the relationship of concepts), can also be a symptom of the early stages of Alzheimer's disease[34][35].
At this stage, apathy may be noted, which remains the most stable neuropsychiatric symptom throughout the disease[36][37][38].
The preclinical stage is also called, depending on the translation of the term "mild cognitive impairment" (MCI) by different authors[39], "mild cognitive decline"[40] or "moderate cognitive impairment"[41], but there are disputes about whether to use the latter name to denote the first stage of Alzheimer's disease or to allocate it to a separate diagnostic unit[42].
Early dementia[edit / edit wiki text]
Progressive memory loss and agnosia in Alzheimer's disease sooner or later lead to confirmation of the diagnosis.
In a small number of patients, it is not memory disorders that come to the fore, but speech disorders, executive functions, perception, or motor disorders (apraxia) [43].
The disease affects different aspects of memory in different ways.
Old memories of one's own life (episodic memory), long memorized facts (semantic memory), implicit memory (unconscious "memory of the body" about a sequence of actions, for example, how to use cutlery) are less susceptible to disorder compared to new facts or memories[44][45].
Aphasia is mainly characterized by a depleted vocabulary and reduced fluency of speech, which generally weakens the ability to verbally and in writing express thoughts.
At this stage of the disease, a person is usually able to adequately operate with simple concepts in speech communication[46][47][48].
When drawing, writing, putting on clothes and other tasks using fine motor skills, a person may seem awkward due to certain problems with coordination and movement planning[49].
As the disease develops, a person is often quite capable of performing many tasks independently, but he may need help or supervision when trying to perform manipulations that require special cognitive efforts[43].
Moderate dementia[edit / edit wiki text]
The ability to act independently decreases due to the progressive deterioration of the condition[43].
Speech disorders become obvious, since with the loss of access to the vocabulary, a person increasingly chooses the wrong words to replace the forgotten ones (paraphrasing).
There is also a loss of reading and writing skills[46][50].
Over time, coordination is increasingly disrupted when performing complex sequences of movements, which reduces a person's ability to cope with most everyday tasks[51].
At this stage, memory problems increase, the patient may not recognize close relatives[52].
Previously intact long term memory is also disturbed[53] and behavioral deviations become more noticeable.
Such neuropsychiatric manifestations as vagrancy, evening exacerbation (English: sundowning)[54], irritability and emotional lability, manifested in crying, spontaneous aggression, in resistance to help and care, are common.
False identification syndrome and other symptoms of delirium develop in about 30 % of patients[36][55].
Urinary incontinence may develop[56].
In the relatives of the patient and the persons caring for him, these symptoms cause stress, which can be mitigated by moving the patient from home care to an inpatient institution[43][57].
Severe dementia[edit / edit wiki text]
In the last stage of Alzheimer's disease, the patient is completely dependent on outside help.
Language proficiency is reduced to the use of single phrases and even individual words, and as a result, speech is completely lost[46].
Despite the loss of verbal skills, patients are often able to understand and reciprocate emotional appeals to them[58].
Although at this stage there may still be manifestations of aggression, much more often the patient's condition is characterized by apathy and exhaustion[43], and from some point he is unable to carry out even the simplest action without someone else's help.
The patient loses muscle mass, moves with difficulty and at a certain stage is unable to leave the bed[59], and then to eat independently[60].
Death usually occurs due to an external factor, such as a bedsore ulcer or pneumonia, and not due to Alzheimer's disease itself[61][62].
Reasons[edit / edit wiki text]
To explain the possible causes of the disease, three main competing hypotheses are proposed: the cholinergic, amyloid and tau hypothesis.
Chronologically, the cholinergic hypothesis was proposed first, according to which the disease is caused by a reduced synthesis of the neurotransmitter acetylcholine.
Currently, this hypothesis is considered unlikely, since medications designed to correct acetylcholine deficiency have low effectiveness, but most of the existing methods of maintenance therapy have been created on its basis.
Other cholinergic effects are assumed, for example, the initiation of large scale amyloid aggregation [63], leading to a generalized neuroinflammatory process[64].
In 1991, the "amyloid hypothesis" was proposed, according to which the underlying cause of the disease is amyloid beta (Aß) deposits[65][66].
The gene encoding the protein (APP) from which beta amyloid is formed is located on chromosome 21.
An interesting fact in support of the amyloid hypothesis is that almost all people who have lived to 40 years of age suffering from Down syndrome (an additional copy of chromosome 21 or its section) have Alzheimer's like pathology [67][68].
In addition, APOE4, the main genetic risk factor for Alzheimer's disease, leads to excessive accumulation of amyloid in brain tissues even before the onset of symptoms[69].
Moreover, in transgenic mice whose bodies produce a mutant form of the human APP gene, fibrillar amyloid plaques are deposited in the brain and other pathological signs characteristic of Alzheimer's disease are noted[70].
An experimental vaccine demonstrated the ability to clear the brain of amyloid plaques in early human trials, but did not have a significant effect on dementia[71].
There was no strong correlation between plaque accumulation and neuronal loss[72].
Currently, the amyloid hypothesis is the main one, but it also does not allow us to explain all the variety of phenomena in Alzheimer's disease.
The accumulation of beta amyloid is not considered to be the direct cause of the disease, but rather a trigger that triggers a sequence of neurodegenerative changes, many of which, including taupathies and neuronal death, manifest only after years.
What exactly triggers the accumulation of beta amyloid, as well as how it affects the tau protein, and how this accumulation can be prevented, remains unknown[73].
Along with the amyloid hypothesis, the tau hypothesis is being studied, according to which the cascade of disorders is triggered by deviations in the structure of the tau protein[66].
Presumably, the strands of hyperphosphorylated tau protein begin to unite with each other, eventually forming neurofibrillary tangles inside nerve cells[74].
This causes the disintegration of microtubules and the collapse of the transport system inside the neuron[75], leading first to a violation of the biochemical signal transmission between cells, and then to the death of the cells themselves[76].
Pathophysiology[edit / edit wiki text]
Histopathological sample of a section of the cerebral cortex with senile plaques.
Silver impregnation.
Neuropathology[edit / edit wiki text]
The disease is characterized by the loss of neurons and synaptic connections in the cerebral cortex and certain subcortical areas.
Cell death leads to pronounced atrophy of the affected areas, including degeneration of the temporal and parietal lobes, areas of the frontal cortex and cingulate gyrus[64].
Both amyloid plaques and neurofibrillary tangles are clearly visible under the microscope during postmortem analysis of brain samples of patients[10].
Plaques are dense, in most cases insoluble deposits of beta amyloid and cellular material inside and outside neurons.
Inside the nerve cells, they grow, forming insoluble twisted plexuses of fibers, often called tangles.
Many elderly people have a certain number of plaques and tangles in the brain, but in Alzheimer's disease there are more of them in certain parts of the brain, such as the temporal lobes[77].
Biochemistry[edit / edit wiki text]
The enzymes cut the amyloid beta precursor into sections, one of which plays a key role in the formation of senile plaques in Alzheimer's disease.
It is noted that Alzheimer's disease is always accompanied by proteinopathy — the accumulation of abnormally folded proteins in the brain tissues — beta amyloid and tau protein[78].
Plaques are formed from small peptides with a length of 39-43 amino acids, called beta amyloid (tj. A beta, Aß).
Beta amyloid is a fragment of a larger precursor protein — APP.
This transmembrane protein plays an important role in the growth of a neuron, its survival and recovery after damage[79][80].
In Alzheimer's disease, for unknown reasons, APP undergoes proteolysis — it is divided into peptides under the influence of enzymes[81].
Beta amyloid filaments formed by one of the peptides stick together in the intercellular space into dense formations known as senile plaques[10][82].
In Alzheimer's disease, changes in the structure of the tau protein lead to the disintegration of microtubules in brain cells.
More specifically, Alzheimer's disease is also referred to as taupathies — diseases associated with abnormal aggregation of tau protein.
Each neuron contains a cytoskeleton, partly composed of microtubules that act like rails, directing nutrients and other molecules from the center to the periphery of the cell, to the end of the axon, and back.
Tau protein, along with several other proteins, is associated with microtubules, in particular, after phosphorylation, it stabilizes them.
In Alzheimer's disease, tau protein undergoes excessive phosphorylation, which causes the protein strands to bind to each other, stick together in neurofibrillary tangles and destroy the neuron transport system[83].
The pathological mechanism[edit / edit wiki text]
It is not known exactly how the violation of synthesis and the subsequent accumulation of beta amyloid peptides causes pathological deviations in Alzheimer's disease[84].
The amyloid hypothesis has traditionally pointed to the accumulation of amyloid beta as the main event triggering the process of neuronal degeneration.
It is believed that the deposits disrupt the homeostasis of calcium ions in the cell and provoke apoptosis[85].
It is known that the place of accumulation of Aß in the neurons of patients is mitochondria, also this peptide inhibits the work of some enzymes and affects the use of glucose[86].
Inflammatory processes and cytokines may play a role in pathophysiology.
Since inflammation is a sign of tissue damage in any disease, in Alzheimer's disease it can play a secondary role in relation to the main pathology or represent a marker of an immune response[87].
Genetics[edit / edit wiki text]
There are three known genes whose mutations mainly allow us to explain the origin of a rare early form, but the common form of Alzheimer's disease does not yet fit into the framework of an exclusively genetic model.
APOE is currently considered the most pronounced genetic risk factor, but variations of this gene are associated with only some cases of the disease[88].
Less than 10 % of cases of the disease under the age of 60 years are associated with autosomal dominant (familial) mutations, which in the total array are less than 0,01 %[88][89][90].
Mutations were found in the genes APP, presenilin 1 and presenilin 2[88], most of them enhance the synthesis of the small protein Abeta42, the main component of senile plaques[91].
In the genus of most patients, there is no predisposition to the disease, but genes may partly determine the risk.
The most well — known genetic risk factor is the inherited E4 allele of the APOE gene, which can be associated with up to half of cases of late sporadic Alzheimer's disease[92].
Geneticists agree that many other genes may contribute to or hinder the development of late Alzheimer's disease to some extent[88].
In total, more than 400 genes were tested for association with this common type of disease[88].
One of the recent examples is a variation of the RELN gene associated with increased morbidity in women[93].
Diagnostics[edit / edit wiki text]
PET brain scans for Alzheimer's disease show a decline in activity in the temporal lobes.
The clinical diagnosis of Alzheimer's disease is usually based on the patient's history (life history), the history of his relatives and clinical observations (hereditary history), while taking into account characteristic neurological and neuropsychological signs and excluding alternative diagnoses[94][95].
In order to distinguish the disease from other pathologies and varieties of dementia, complex methods of medical imaging can be used — computed tomography, magnetic resonance imaging, single photon emission computed tomography or positron emission tomography[96].
For a more accurate assessment of the state, intelligent functions, including memory, are tested.
Medical organizations develop diagnostic criteria in order to facilitate the diagnosis of a practitioner and standardize the process of making a diagnosis.
Sometimes the diagnosis is confirmed or established postmortem by histological analysis of brain tissues[97].
Diagnostic criteria[edit / edit wiki text]
The American National Institute of Neurological and Communication Disorders and Stroke (NINDS) and the Alzheimer's Association have compiled the most commonly used set of criteria for the diagnosis of Alzheimer's disease[98].
According to the criteria, in order to make a clinical diagnosis of possible Alzheimer's disease, it is necessary to confirm the presence of cognitive impairment and suspected dementia syndrome during neuropsychological testing.
For the final confirmation of the diagnosis, a histopathological analysis of brain tissues is necessary, and during the reconciliation of lifetime diagnoses according to criteria with post mortem analysis, good statistical reliability and verifiability were noted[99].
Most often, disorders in Alzheimer's disease affect eight domains: memory, language skills, the ability to perceive the environment, constructive abilities, orientation in space, time and self identity, problem solving skills, functioning, self sufficiency.
These domains are equivalent to the NINCDS AD criteria The RDA listed in DSM IV TR[100][101].
Diagnostic methods[edit / edit wiki text]
Neuropsychological screening testing can help in the diagnosis of Alzheimer's disease, in which patients copy shapes, remember words, read, perform arithmetic operations.
PET scan: In Alzheimer's disease, the Pittsburgh compound B injected into the body accumulates in the brain, anchoring itself to the deposits of beta amyloid (left).
On the right is the brain of an elderly person without signs of Alzheimer's disease.
Neuropsychological tests, for example, MMSE, are widely used to assess cognitive impairments that should be present in the disease.
To obtain reliable results, more detailed test sets are required, especially in the early stages of the disease[102][103].
At the beginning of the disease, a neurological examination usually does not show anything unusual, except for obvious cognitive abnormalities that may resemble ordinary dementia.
In view of this, an extended neurological study is important for the differential diagnosis of Alzheimer's disease and other diseases[104].
A conversation with family members is also used in assessing the course of the disease, since relatives can provide important information about the level of daily activity of a person and about the gradual decline of his thinking abilities[105].
Since the patient himself usually does not notice violations, the point of view of the people caring for him is especially important[106].
At the same time, in many cases, the early symptoms of dementia go unnoticed in the family and the doctor receives inaccurate information from relatives[107].
Additional tests enrich the picture with information about some aspects of the disease or allow you to exclude other diagnoses.
A blood test can reveal alternative causes of dementia[104], which sometimes even respond to therapy that reverses the symptoms[108].
Psychological tests are also used to detect depression, which can both accompany Alzheimer's disease and cause cognitive decline[109][110].
SPECT and PET imaging equipment, if available, can be used to confirm the diagnosis in conjunction with other assessment methods, including mental status analysis[111].
In people who already suffer from dementia, SPECT, according to some data, allows more effectively differentiating Alzheimer's disease from other causes, compared with standard testing and anamnesis[112].
The opportunity to observe the deposits of amyloid beta in the brain of living people appeared thanks to the creation of the University of Pittsburgh composition B (PiB), which binds to amyloid deposits when injected into the body.
The short lived radioactive isotope carbon 11 in the compound allows determining the distribution of this substance in the body and obtaining a picture of amyloid deposits in the patient's brain using a PET scanner[113].
It has also been shown that the content of beta amyloid or tau protein in the cerebrospinal fluid can be an objective marker of the disease[114].
These two new methods have led to proposals for the development of new diagnostic criteria[98][104].
Prevention of the disease[edit / edit wiki text]
Intellectual activity, including a passion for playing chess, and regular communication correlate with a reduced risk of developing Alzheimer's disease, according to epidemiological studies, but a causal relationship has not yet been proven.
International studies designed to assess how much a particular measure can slow down or prevent the onset of the disease often give contradictory results.
To date, there is no solid evidence of a preventive effect of any of the factors considered[115].
At the same time, epidemiological studies suggest that some correctable factors — diet, risk of cardiovascular diseases, medication intake, mental activity, and others — are associated with the likelihood of developing the disease.
However, real evidence of their ability to prevent the disease can be obtained only in the course of additional research, which will include clinical studies[116].
The ingredients of the Mediterranean diet, including fruits and vegetables, bread, wheat and other cereals, olive oil, fish and red wine, may be able to individually or collectively reduce the risk and mitigate the course of Alzheimer's disease[117].
Taking some vitamins, including B12, B3, C and folic acid, has been associated with a reduced risk of developing the disease in some studies[118], but other studies indicate that there is no significant effect on the onset and course of the disease and the likelihood of side effects[119].
Curcumin, contained in a common spice, in a study on mice showed some ability to prevent certain pathological changes in the brain[120].
Caprylic acid, contained in coconut oil, reduces the number of amyloid plaques in the neurons of the brain stem.
In the process of metabolism of this substance, ketone bodies are formed, which are involved in the energy processes of the brain.
Laboratory experiments are supported by practice.
There is a famous book by Dr. Mary Newport, " What if this is a medicine?".
In it, she describes observations of her husband, who suffers from Alzheimer's disease.
Against the background of using coconut oil for a month, he began to successfully cope with simple psychological tests and resumed his participation in household chores[121].
Risk factors for cardiovascular diseases, such as high cholesterol and hypertension, diabetes, smoking, are associated with an increased risk and a more severe course of Alzheimer's disease[122][123], but cholesterol lowering drugs (statins) have not shown effectiveness in preventing it or improving the condition of patients[124][125].
Long term use of nonsteroidal anti inflammatory drugs is associated with a reduced probability of developing the disease in some people[126].
Other medications, such as hormone replacement therapy in women, are no longer considered effective in preventing dementia[127][128].
A systematic review of ginkgo biloba conducted in 2007 indicates the inconsistent and inconclusive nature of the presented evidence of the drug's effect on cognitive impairment[129], and another study indicates that there is no effect on morbidity[130].
Some studies indicate an increased risk of developing Alzheimer's disease in those people whose work is associated with exposure to magnetic fields[131][132], ingestion of metals, especially aluminum[133][134], or the use of solvents[135].
Some of these publications have been criticized for the poor quality of the work[136], besides, other studies have not found a link between environmental factors and the development of Alzheimer's disease[137][138][139][140].
Intellectual activities, such as reading, board games, solving crosswords, playing musical instruments, regular communication, may be able to slow down the onset of the disease or mitigate its development[141][142].
Bilingual proficiency is associated with a later onset of Alzheimer's disease[143].
In a review published in 2015, Canadian researchers indicate that psychotechnics based on the practice of mindfulness[en] can prevent the onset of mild cognitive impairment and the development of Alzheimer's disease[144].
According to recent studies, a decrease in cognitive functions in Alzheimer's disease correlates with the presence of periodontitis in a patient.[145]
Thus, according to the data of the Institute of Dentistry at King's College London, published in the journal PLOS One, gum disease is associated with a six fold decrease in cognitive functions (a sample of 59 people, the duration of observation is 6 months).
Also, the journal "News of Medicine Today" reported on a similar study in 2014, when the bacterium pathogen of periodontitis Porphyromonas gingivalis was identified in a brain biopsy of patients with Alzheimer's disease.
Therapy and care[edit / edit wiki text]
There is no cure for Alzheimer's disease; the available therapies can slightly affect the symptoms, but are essentially palliative measures.
Pharmacological, psychosocial and patient care measures can be distinguished from the whole range of measures.
Pharmacotherapy[edit / edit wiki text]
Three dimensional structure of donepezil, an acetylcholinesterase inhibitor used for symptomatic therapy.
The molecular structure of memantine, a drug approved for use in Alzheimer's disease.
Currently, there are no drugs that can reverse or at least slow the development of Alzheimer's disease.
Regulatory agencies such as the FDA and EMEA have approved four drugs for the treatment of cognitive impairment in Alzheimer's disease — three central acting cholinesterase inhibitors and memantine, an NMDA antagonist.
A well known sign of Alzheimer's disease is a decrease in the activity of cholinergic neurons[146].
Central acting cholinesterase inhibitors reduce the rate of destruction of acetylcholine( ACh), increasing its concentration in the brain and compensating for the loss of ACh caused by the death of cholinergic neurons[147].
The first such inhibitor approved for use in Alzheimer's disease was takrin [en], but in 2012 its use in the United States was banned due to hepatotoxic and other side effects[148][149].
As of 2008, doctors used such ACh inhibitors as donepezil[150], galantamine[151], and rivastigmine (in the form of tablets[152] and a patch[153]).
There is evidence of the effectiveness of these drugs at the initial and moderate stages[154], as well as some grounds for their use at a late stage.
Only donepezil is approved for use in the onset of severe dementia[155].
The use of these drugs in mild cognitive impairment does not slow down the onset of Alzheimer's disease[156].
Among the side effects of drugs, the most common are nausea and vomiting associated with an excess of cholinergic activity, they occur in 1-10% of patients and can be weakly or moderately expressed.
Muscle spasms, bradycardia, decreased appetite, weight loss, and increased acidity of gastric juice are less common[157].
Currently, another cholinesterase inhibitor, gupercin, is being studied, which is also an antagonist to NMDA receptors and can mitigate cognitive impairment in patients, but has not yet passed full fledged clinical trials[158].
Excitatory neurotransmitter glutamate plays an important role in the nervous system, but its excess leads to excessive activation of glutamate receptors and can cause cell death.
This process, called excitotoxicity, is observed not only in Alzheimer's disease, but also in other conditions, for example, in Parkinson's disease and multiple sclerosis[159].
A drug called Memantine [160], originally used in the treatment of influenza, inhibits the activation of glutamate NMDA receptors[159].
Memantine has been shown to be moderately effective in moderate to severe Alzheimer's disease, but it is not known how it acts at an early stage[161].
Mild side effects are rarely observed, including hallucinations, confusion, dizziness, headache and fatigue[162].
In combination with donepezil, memantine demonstrates "statistically significant, but clinically barely noticeable effectiveness" in acting on cognitive indicators[163].
In patients whose behavior is a problem, antipsychotics can moderately reduce aggression and affect psychosis.
At the same time, these drugs cause serious side effects, in particular, cerebrovascular complications, motor disorders and a decrease in cognitive abilities, which excludes their daily use[164][165].
With prolonged administration of antipsychotics in Alzheimer's disease, there is an increased mortality [165].
Psychosocial intervention[edit / edit wiki text]
"Sensory integrative therapy": a special sensory room (English snoezelen) is used for emotionally oriented assistance to people suffering from dementia.
Psychosocial intervention complements pharmacological intervention and can be divided into the following approaches
behavioral emotional cognitive stimulant oriented
The effectiveness of the intervention has not yet been covered in the scientific literature, moreover, the approach itself does not apply to Alzheimer's disease, but to dementia in general[166].
Behavioral intervention is aimed at identifying the prerequisites and consequences of problematic behavior and working to correct them.
When using this approach, there was no improvement in the overall level of functioning[167], but it is possible to mitigate some individual problems, such as urinary incontinence[168].
There is not enough qualitative data on the impact of methods of this direction on other behavioral deviations, such as wandering, [169][170].
Interventions affecting the emotional sphere include reminiscence therapy (RT), validation therapy, supportive psychotherapy, sensory integration ("snuzelen"), and "simulated presence therapy" (SPT).
Supportive psychotherapy has hardly been studied by scientific methods, but some clinical workers believe that it provides benefits when trying to help patients with mild illness adapt to the disease[166].
In memory therapy (RT), patients discuss their experiences face to face with a therapist or in a group, often using photographs, household items, old music and archival audio recordings, and other familiar objects from the past.
Although the number of qualitative studies of the effectiveness of RT is small, it is possible that this method has a positive effect on the patient's thinking and attitude[171].
The simulation of presence, based on attachment theories, involves playing audio recordings with the voices of close relatives.
According to preliminary data, the level of anxiety decreases in patients undergoing SPT, their behavior becomes calmer[172][173].
Validation therapy is based on the recognition of the reality and personal truth of another person's experiences, and during sensory integration sessions, the patient performs exercises designed to stimulate the senses.
There is not much data to support these two methods[174][175].
Reality orientation, cognitive retraining, and other cognitively oriented therapies are used to reduce cognitive deficits.
Orientation in reality consists in presenting information about the time, location and personality of the patient in order to facilitate their awareness of the situation and their own place in it.
In turn, cognitive retraining is carried out to improve the impaired abilities of the patient, who is given tasks that require mental stress.
There was some improvement in cognitive abilities when using both the first and second methods[176][177], but in some studies this effect disappeared over time and negative manifestations were noted, for example, patient disappointment[166].
Stimulating methods of therapy include art therapy, music therapy, as well as types of therapy in which patients communicate with animals, engage in physical exercises and any other restorative activity.
According to studies, stimulation has a moderate effect on behavior and mood, and even less on the level of functioning.
However, such therapy is carried out mainly to improve the daily life of patients[166].
Care and supervision[edit / edit wiki text]
Detailed consideration of the topic: Aspects of dementia care
Care and supervision of the patient is extremely important because of the incurable and degenerative nature of the disease.
This role is often assumed by a spouse or a close relative[178].
Such a heavy burden strongly affects the social, psychological, economic and other aspects of the life of a person engaged in caring for a patient[179][180][181].
Since Alzheimer's disease is incurable and gradually negates a person's ability to take care of himself, patient care actually forms the basis of therapy and deserves special attention throughout the disease.
In the early and moderate stages of the disease, it is possible to increase the patient's safety and ease the burden of caring for him by making changes in the environment and lifestyle[182][183].
Among such measures is the transition to a simple routine daily routine, hanging safety locks, labels on household accessories with an explanation of how to use them[166][184][185].
The patient may lose the ability to eat independently, in this case it is necessary to grind the food or transfer it to a porridge like state[186].
If there are problems with swallowing food, feeding through a tube may be required.
In this case, family members and service workers face an ethical question about how long they should continue feeding, how effective it is from a medical point of view[187][188].
The need to physically fix the patient rarely occurs, but in some situations it is necessary to resort to fixation in order to protect the patient from harming himself or others[166].
As the disease develops, various complications may occur, for example, diseases of the teeth and oral cavity, bedsores, nutritional disorders, hygiene problems, respiratory, eye or skin infections.
They can be avoided with careful care, but if they occur, professional intervention is required[62][189].
Relieving the patient's well being before approaching death becomes the main task at the last stage of the disease[190].
Forecast[edit / edit wiki text]
In the early stages, Alzheimer's disease is difficult to diagnose.
A certain diagnosis is usually made when cognitive disorders begin to affect a person's daily activity, although the patient himself may still be able to live an independent life.
Gradually, mild problems in the cognitive sphere are replaced by increasing deviations, both cognitive and other, and this process inexorably puts a person into a state dependent on someone else's help[43].
Life expectancy in the group of patients is reduced[7][191][192], and after the diagnosis, they live on average about seven years[7].
Less than 3 % of patients remain alive for more than fourteen years[8].
Such signs as increased severity of cognitive impairment, reduced level of functioning, falls, deviations during neurological examination are associated with increased mortality.
Other concomitant disorders, such as cardiac problems, diabetes, a history of alcohol abuse, are also associated with reduced survival[191][193][194].
The earlier the onset of Alzheimer's disease, the more years on average a patient manages to live after the diagnosis, but when compared with healthy people, the total life expectancy of such a person is especially low[192].
The prognosis for survival in women is more favorable than in men[8][195].
Mortality in patients in 70 % of cases is due to the disease itself[7], while most often the direct causes are pneumonia and dehydration of the body.
Cancer in Alzheimer's disease is less common than in the general population[7][195].
Culture and society[edit / edit wiki text]
The burden on society[edit / edit wiki text]
Among the diseases that impose a great burden on society in developed countries, Alzheimer's disease and dementia in general can occupy one of the first places[17][18].
In developing countries, such as Argentina[196], and newly developed countries (South Korea)[197], public costs are also high and continue to grow.
They are likely to rise even higher as society ages and become an important social problem.
The costs include direct medical costs for the maintenance of nursing homes and non medical costs for home care of the patient, and indirect costs, for example, loss of productivity both the patient and the person caring for him[18].
The estimates given in the studies vary, but in general, the cost of dementia around the world can be about $ 160 billion[198], and in the United States — about $ 100 billion annually[18].
The largest public costs go to pay for long term professional care of the patient, in particular, institutionalization, this requires up to two thirds of the total amount of funds[17].
Home care is also expensive[17], especially when taking into account informal family expenses, including time spent and lost wages[199].
Costs increase in severe dementia and behavioral disorders[200] due to the need to devote more time to patient care[199].
Therefore, any therapy that can slow down the decline of cognitive abilities, postpone institutionalization or reduce the number of hours devoted to patient care will be useful from the economic side.
The economic assessment of the existing methods of therapy indicates positive results[18].
Patient care[edit / edit wiki text]
Detailed consideration of the topic: Aspects of dementia care
The main care for the patient is usually taken by a spouse or a close relative[178], thereby shouldering a heavy burden, since care requires physical exertion, financial costs, affects the social side of life and is psychologically very painful[179][180][181].
Both patients and relatives usually prefer home care[201].
At the same time, it is possible to postpone or completely avoid the need for more professional and expensive care[201][202], but two thirds of residents in nursing homes still suffer from dementia[166].
Among those caring for a dementia patient, there is a high level of somatic diseases and mental disorders[203].
If they live under the same roof with a patient, if the patient is a spouse, if the patient becomes depressed, behaves inappropriately, hallucinates, suffers from sleep disorders and is unable to move normally — all these factors, according to research, are associated with an increased number of psychosocial problems[204][205].
The caregiver also has to spend an average of 47 hours a week with the patient, often at the expense of working time, while the cost of care is high.
Direct and indirect costs of patient care in the United States average from$ 18,000 to $ 77,500 per year, according to various studies[199][206].
According to research, the psychological health of people caring for patients can be strengthened by methods of cognitive behavioral therapy and training in strategies to counteract stress, both individually and in groups[179][207].
Famous people, mass media, works of literature and cinema[edit / edit wiki text]
Charlton Heston and Ronald Reagan at a meeting at the White House, 1981.
Both of them fell ill with Alzheimer's disease by the end of their lives.
Alzheimer's disease affects many people, not bypassing celebrities, including such famous ones as former US President Ronald Reagan and Irish writer Iris Murdoch.
The fact of the illness of both was not only widely covered in the media, but also served as the basis for scientific articles, the authors of which analyze the progressive weakening of the cognitive functions of these public persons[208][209].
Other famous victims of the disease were football player Ferenc Puskas[210], former British Prime Minister Harold Wilson, Spanish Prime Minister Adolfo Suarez[211][212], actors Peter Falk[213], Rita Hayworth[214], Annie Girardot and Charlton Heston[215], writer Terry Pratchett[216].
Alzheimer's disease is also reflected in films, including "Iris" (2001)[ 217], based on the memoirs of John Bailey, the husband of Iris Murdoch[218]; "Diary of Memory" (2004)[219] based on the novel of the same name by Nicholas Sparks[220];
"I donot want to forget" ("Eraser in my head") (2004) [221]; "Tanmatra" (2005); [222] "Memory of Tomorrow" (2006)[223] based on the novel of the same name by Hiroshi Ogiwara[224]; "Far from her" (2006), based on the story of Alice Munro "The Bear crossed the mountain"[225], the TV series "El Internado Laguna Negra" (Black Lagoon; season 7)(2007), "Cortex" (2008), "Rise of the Planet of the Apes" (2011), "Friendship Sex" (2011), "The Iron Lady" (2011), "The divorce of Nader and Simin" (2011), the TV series "Table in the corner", the TV series "Anatomy of Passion", the TV series "Theory of Lies" 2009-2011 season 3, episode 7, the TV series "Detective Nash Bridges", the TV series "They were confused in the maternity hospital" (season 4), the films "Deep Blue Sea", "Ben X" (2007), black and white film "Nebraska" (2013), "Honey in the Head"(2014).
Documentaries include such works as" Malcolm and Barbara: A Love Story "(1999) and" Malcolm and Barbara: The Farewell of Love", with the participation of Malcolm Pointon[226].
Research directions[edit / edit wiki text]
Main article: Clinical studies in Alzheimer's disease
In 2008, more than 400 pharmaceutical products were being tested in various countries around the world.
About a quarter of them passed the phase III clinical trials, at the successful completion of which the issue of using the drug is considered by regulatory authorities[227].
There is a direction of clinical research aimed at correcting basic pathological changes.
One of the typical targets for drugs undergoing testing are accumulations of beta amyloid, which need to be reduced.
Methods such as immunotherapy or vaccination against amyloid protein are being tested.
Unlike the usual vaccination carried out in advance, in the case of Alzheimer's disease, the vaccine will be administered to patients who have already received a diagnosis.
According to the researchers ' concept, the patient's immune system should learn to recognize and attack amyloid deposits, reducing their size and facilitating the course of the disease[228].
A specific example of a vaccine is the ACC 001[229][230] molecule, whose clinical trials were frozen in 2008[231].
Another similar remedy is bapinizumab, an artificial antibody identical to a natural anti amyloid antibody[232].
Neuroprotective agents, for example, AL 108[233], and inhibitors of metal protein interactions, such as PBT2[234], are also under development.
The hybrid protein etanercept, acting as a TNF inhibitor, shows promising results[235].
In experiments on mice with a model of Alzheimer's disease, very promising drugs were found that improved cognitive abilities, such as the EPPS compound that protects nerve tissue by actively destroying amyloid plaques[236], as well as the drug J147[237] and the anti asthmatic drug Montelukast[238], which demonstrated an improvement in the brain state similar to rejuvenation.
During clinical trials conducted in 2008, positive changes in the course of the disease were noted in patients at the initial and moderate stages under the influence of tetramethylthionine chloride, which inhibits the aggregation of tau protein[239][240], and antihistamine dimebone[241].
In order to provide scientists from different countries with the opportunity to exchange ideas and propose hypotheses, as well as to provide everyone interested with information about the latest scientific research, the online project Alzheimer Research Forum was created.
In 2014, a team led by Kim Doo yong and Rudolf Tanzi managed to create a three dimensional culture of nervous tissue based on human stem cells in vitro, in which degenerative changes associated with the accumulation of beta amyloid formations and taupathies were experimentally reproduced[242].
One of the directions of research is to study the course of the disease in patients belonging to different races.
A group of scientists led by Lisa Barnes organized a study in which 122 people took part, of which 81 people belonged to the Caucasian race and 41 to the Black race.
Scientists examined the brain tissue of patients.
In 71 % of patients of the Black race, signs of other pathologies besides Alzheimer's disease were found.
Among the representatives of the Caucasian race, this indicator was 51 %.
In addition, African Americans were more likely to have blood vessel diseases.
Medications that are currently used to treat Alzheimer's disease affect only a certain type of pathology.
The obtained data on the mixed picture of the disease in representatives of the Black race will help in creating new methods of treatment for this group of patients[243].
In 2016, biologists at the RIKEN MIT Center for Neural Circuit Genetics published the results of their study.
They found that by irritating the areas of the brain responsible for memory with light, it is possible to stimulate the growth of neural connections.
This helps to improve the process of extracting memories, which suffers from a neuro degenerative pathology, such as Alzheimer's disease[244].
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