Alzheimer’s Disease

What is Alzheimer’s Disease?

Alzheimer’s disease (also senile dementia of the Alzheimer’s type) is the most common form of dementia, an incurable degenerative disease, first described in 1906 by the German psychiatrist Alois Alzheimer. As a rule, it is found in people over 65, but there is also early Alzheimer’s disease – a rare form of the disease. The global incidence for 2006 was estimated at 26.6 million people, and by 2050 the number of patients could grow fourfold.

For each person, the disease proceeds in its own way, but there are a number of common symptoms. The first noticeable manifestations are usually mistakenly associated with advanced age or explained by the effect of stress. Most often, in the early stages, a memory disorder is recognized, this symptom may manifest itself, for example, inability to recall recently learned information. When they go to a doctor and suspect Alzheimer’s disease, they usually analyze their behavior, make a series of cognitive tests, if possible, carry out magnetic resonance imaging (MRI) to clarify the diagnosis. With the development of the disease, symptoms such as confusion, irritability and aggressiveness, mood fluctuations appear, the ability to speak and understand what is said (aphasia) is impaired, there is a loss of long-term memory and the patient’s general withdrawal from work as the consciousness wanes. The gradual loss of body functions leads to death. Individual prognosis is difficult due to variations in the duration of the disease, which may develop latently over a long time before the symptoms become noticeable and the diagnosis is made. The average life expectancy after diagnosis is about seven years, less than three percent of patients live more than fourteen years.

Currently, a complete understanding of the causes and course of Alzheimer’s disease has not been achieved. Research suggests the association of disease with plaque accumulation and neurofibrillary tangles in brain tissue. Modern methods of therapy only slightly alleviate the symptoms, but so far they do not allow either to slow down or stop 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. There are many ways to prevent Alzheimer’s disease, but their effects on the course of the disease and its severity are not noted. Both for prevention and for fighting disease, it is often recommended to exercise, stimulate thinking and stick to a balanced diet.

Alzheimer’s disease belongs to diseases that impose the heaviest financial burden on society in developed countries.

Epidemiology
The two main indicators used in epidemiological studies are the incidence and prevalence of the disease (pain). Incidence reflects the number of new cases per unit of person-time (usually the number of new cases per thousand person-years), and soreness refers to the total number of people affected by the disease in a population at a specific point in time.

Cohort longitudinal studies (during which an initially healthy population has been monitored for many years) show an incidence of 10–15 new cases per thousand person-years for all types of dementia and 5–8 cases for Alzheimer’s disease, which is about half of the total the number of annual diagnoses. Older age is the main risk factor, which is reflected in statistics: for every five years after 65 years of age, the risk index increases approximately twice, growing from 3 cases in 65 years to 69 cases per thousand person-years to 95 years. There are also sex differences – women are more likely to develop Alzheimer’s disease, especially after 85 years.

The prevalence of the disease in the population depends on various factors, including morbidity and mortality. As the incidence increases with age, it is necessary to take into account the average age of the population in the studied area. In the United States, as of 2000, about 1.6% of the population, both in general and in the group of 65-74 years old, had Alzheimer’s disease. In the group of 75-84 years, this figure was already 19%, and among citizens whose age exceeded 84 years, the prevalence of the disease was 42%. In less developed countries, the prevalence of the disease is lower. According to WHO, in 2005, 0.379% of the world’s population suffered from dementia, and the forecast for 2015 reaches a value of 0.441% and an even larger percentage of the population, 0.556%, may be affected by the disease by 2030. The authors of other works come to similar conclusions. Another study suggests that in 2006, the prevalence of the disease in the world was 0.40% (range 0.17-0.89%, the absolute number – 26.6 million people, with a spread of 11.4-59.4 million) and predicts that the share index will increase threefold, and the absolute number of patients is quadrupled by 2050.

Causes of Alzheimer’s Disease

Microscopic image of a neurofibrillary tangle formed by hyperphosphorylated tau protein.

The explanation of the possible causes of the disease is proposed in three main competing hypotheses. According to the oldest “cholinergic hypothesis” on which most of the existing therapies are based, Alzheimer’s disease is caused by a reduced synthesis of the neurotransmitter acetylcholine. Support for this hypothesis has weakened, since drugs designed to correct acetylcholine deficiency are of low efficiency. Other cholinergic effects are suggested, for example, initiation of large-scale amyloid aggregation leading to a generalized neuro-inflammatory process.

In 1991, the “amyloid hypothesis” was proposed, according to which the basic cause of the disease is beta-amyloid deposits (Aβ). 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 surviving 40 years old people suffering from Down syndrome (an additional copy of chromosome 21 or its area), Alzheimer-like pathology is found. In addition, APOE4, the main genetic risk factor for Alzheimer’s disease, leads to excessive accumulation of amyloid in brain tissue before the onset of symptoms. Moreover, in transgenic mice, in the body of which the mutant form of the human APP gene is produced, a fibrillar amyloid plaque is deposited in the brain and other pathological signs characteristic of Alzheimer’s disease occur. 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.

Not found a confident correlation of plaque accumulation with neuron loss. This speaks in support of the tau hypothesis, according to which a cascade of disorders is triggered by abnormalities in the structure of the tau protein. Presumably, the threads of the hyperphosphorylated tau protein begin to unite with each other, eventually forming neurofibrillary tangles inside the nerve cells. This causes the disintegration of microtubules and the collapse of the transport system inside the neuron, leading first to disruption of biochemical signaling between cells, and then to the death of the cells themselves.

Pathogenesis During Alzheimer’s Disease

Studies of the pathogenesis and pathology of Alzheimer’s disease at the moment with great certainty indicate that Alzheimer’s disease is most likely pathogenetic in terms of heterogeneity. So, one of the hypotheses of Alzheimer’s disease is based on intracerebral amyloid deposition, which is typical, however, not for all cases of Alzheimer’s disease. Intracerebral deposition of abnormal amyloid protein, or b-amyloid protein, in addition to Alzheimer’s disease, is possible with Down syndrome, congenital cerebral hematomas with Dutch amyloidosis and normal aging. b-amyloid protein is an insoluble derivative of a large transmembrane glycoprotein, or amyloid precursor protein (APP). The mechanism of deposition of b-amyloidprotein is currently unknown. One of the proposed hypotheses is a point gene mutation, as a result of which a pathological β-amyloid protein is formed. However, this hypothesis today is not fully proven.

A number of predisposing factors can be noted leading to the transition of soluble APP to insoluble b-amyloid protein. This, in particular, the shift in the pH of the extracellular environment in the acidic side, the failure of mitochondrial oxidation, the increase in the content of free radicals. M.D.Smyth et al. suggest that in Alzheimer’s disease there is a decrease in the activity of lysosomal hydrolases, which, in turn, may be the cause of impaired resorption of b-amyloid protein. However, in the literature on the pathology of Alzheimer’s disease, there are also opposite results.
The fibrillar amyloid is deposited in the walls of the cerebral vessels and in the brain parenchyma in the form of a so-called. “Senile plaques”. The deposition of amyloid leads to the death of neurons located near senile plaques. One of the hypotheses that explain this phenomenon is the activation of the b-amyloid protein of calcium neuronal channels (with an increase in the content of intracellular calcium) and the development of free radical oxidation of neuronal membranes. A.J. Anderson et al. suggest that neuronal and non-neuronal cell death in Alzheimer’s disease is a result of the expression of apoptosis gene inducers (cjun) due to the effects of APP and b-amyloid protein, which is consistent with the activation of NMD-receptors followed by an increased Ca2 + entry into the cell and the development of free radical oxidation.

It is also possible and direct toxic effect of amyloid on glial structures. A. McRae et al. It was experimentally shown that in Alzheimer’s disease microglia macrophages are activated as a result of the supposedly direct toxic action of amyloid. These data are confirmed by other researchers. The result of the activation of microglia can be the destruction of neurons. R.B. Banati et al. the results indicate the ability of activated microglia in Alzheimer’s disease to denovo synthesize b-amyloid protein, which, accordingly, can ensure the cyclical nature and progression of the pathological process.

Recent studies indicate the possible involvement of complement protein in the classical way, leading to the formation of senile plaques. The spherical protein SP 40,40 of the human complement system in various forms is part of the b-amyloid protein and is capable of attacking the complement, which also contains S protein, through the membrane. Activation of the classical complement cascade implements cell lysis. In combination with reactive changes of microglia and an increase in the content of cytokines, these changes, in turn, can lead to the development of neuronal degeneration. According to A. Afagh et al., Senile plaques that are positive for the presence of complement are typical of Alzheimer’s disease and are not found in the absence of dementia. Microglial reactivity and astrogliosis correlate with the presence of complement-positive amyloid deposits.

Another characteristic morphological feature of Alzheimer’s disease is intracellular intraneuronal plexus, which are modified cytoskeleton microtubules. The main composition of the neurofibrillary tangles is hyperphosphorylated tau protein (tauP). Neurofibrillary plexuses are not strictly a morphological criterion for Alzheimer’s disease; their presence has been described in various cerebral degenerations (frontotemporal atrophy, progressive supranuclear palsy, etc.). Most researchers at the moment deny the independent pathogenetic significance of TauP; most likely, neurofibrillary plexuses are the result of massive and generalized brain cell death.

One of the possible components of the pathogenesis of Alzheimer’s disease is the formation of pathological forms of apolipoprotein E. So, according to T. Lehtimaki et al., The likelihood of Alzheimer’s disease is 18 times higher in individuals wearing heterozygous forms of apolipoprotein E E4. These data are confirmed by other researchers. The high affinity of the pathological forms of apolipoprotein E to the amyloid protein and participation in transport of Pau may possibly contribute to the development of morphological changes characteristic of Alzheimer’s disease.

Symptoms of Alzheimer’s Disease

The course of the disease is divided into four stages, with a progressive pattern of cognitive and functional disorders.

Predecession
The first symptoms are often confused with aging or stress response. The earliest cognitive difficulties are identified in some people with detailed neurocognitive testing eight years before diagnosis. These initial symptoms can affect the performance of the most complex daily tasks. The most noticeable memory disorder, manifested in the difficulty when trying to remember recently learned facts and in the inability to absorb new information. 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. At this stage, apathy may be noted, which remains the most persistent neuropsychiatric symptom throughout the course of the disease. Also, the preclinical stage is called “mild cognitive impairment,” but there is debate about whether to use the latter name to denote the first stage of Alzheimer’s disease or to separate it into a separate diagnostic unit.

Early dementia
Progressive loss of memory and agnosia in Alzheimer’s disease sooner or later lead to confirmation of the diagnosis. In a small number of patients, not memory disorders, but speech, executive function, perception, or motor impairment (apraxia) come to the fore. Disease has a different effect on various aspects of memory. Old memories of one’s own life (episodic memory), long-learned facts (semantic memory), implicit memory (unconscious “body memory” about the sequence of actions, for example, how to use cutlery) are less prone to frustration than new facts or memories. Aphasia is mainly characterized by the impoverishment of vocabulary and reduced fluency, which generally weakens the ability to verbal and written expression of thoughts. At this stage of the disease, a person is usually able to adequately operate with simple concepts in verbal communication. When drawing, writing, putting on clothes and other tasks using fine motor skills, a person may seem awkward because of certain problems with the coordination and planning of movements. As the disease progresses, a person is often quite capable of performing many tasks independently, but he may need help or supervision when trying to carry out manipulations that require special cognitive efforts.

Mild dementia
The ability for independent action is reduced due to progressive deterioration. Speech disorders become obvious, as with the loss of access to the vocabulary a person more and more often selects the wrong words to replace the forgotten (paraphrase). There is also a loss of reading and writing skills. Over time, coordination is more and more disturbed when performing complex sequences of movements, which reduces a person’s ability to cope with most everyday tasks. At this stage, memory problems are amplified, and the patient may not recognize close relatives. Formerly, intact, long-term memory is also impaired and behavioral deviations become more noticeable. Neuropsychiatric manifestations such as vagrancy, evening aggravation (irritability), irritability and emotional lability, manifested in crying, spontaneous aggression, or resistance to care, are common. False identification syndrome and other symptoms of delusions develop in about 30% of patients. Incontinence may develop. In the relatives of the patient and the caregivers, these symptoms cause stress, which can be mitigated by moving the patient from home care to a hospital.

Severe dementia
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. Despite the loss of verbal skills, patients are often able to understand and reciprocate emotional appeals to them. Although at this stage there may still be manifestations of aggression, much more often the patient’s condition is characterized by apathy and exhaustion, and at some point he is unable to carry out even the simplest action without help from others. The patient loses muscle mass, moves with difficulty and at a certain stage is not able to leave the bed, and then eat independently. Death usually occurs due to a third-party factor, such as a pressure ulcer or pneumonia, and not due to Alzheimer’s disease itself.

Diagnosis of Alzheimer’s Disease

PET scans of the brain in 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 (a history of life), the history of his relatives and clinical observations (hereditary history), taking into account the characteristic neurological and neuropsychological signs and excluded alternative diagnoses. In order to distinguish the disease from other pathologies and varieties of dementia, complex medical imaging techniques such as computed tomography, magnetic resonance imaging, photon emission computed tomography or positron emission tomography can be used. [90] For a more accurate assessment of the state, intellectual functions are tested, including memory. Medical organizations develop diagnostic criteria in order to facilitate the diagnosis of the practitioner and standardize the process of diagnosis. Sometimes the diagnosis is confirmed or established posthumously by histological analysis of brain tissue.

Diagnostic criteria for Alzheimer’s disease
The National Institute of Neurological and Communicative Disorders and Stroke (NINDS) and the Alzheimer’s Disease Association formed the most frequently used set of criteria for diagnosing Alzheimer’s disease. According to the criteria, for making a clinical diagnosis of possible Alzheimer’s disease, it is required to confirm the presence of cognitive impairment and presumptive dementia syndrome during neuropsychological testing. For final confirmation of the diagnosis, a histopathological analysis of brain tissues is necessary, and during the verification of in vivo diagnoses by criteria with posthumous analysis, good statistical reliability and verifiability were noted. Most often, disorders in Alzheimer’s disease affect eight domains: memory, language skills, ability to perceive the environment, constructive abilities, orientation in the space of time of his own personality, problem solving skills, functioning, self-sustainment.

These domains are equivalent to the NINCDS-ADRDA criteria listed in the DSM-IV-TR.

Diagnostic tools
In the diagnosis of Alzheimer’s disease can help neuropsychological screening testing, in which patients copy figures, memorize words, read, perform arithmetic operations.

PET scan: In Alzheimer’s disease, the Pittsburgh composition B introduced into the body accumulates in the brain, becoming attached to beta-amyloid deposits (left). On the right is an older person’s brain with no signs of Alzheimer’s disease.
Neuropsychological tests, such as MMSE, are widely used to assess cognitive impairment that must be present in a disease. To obtain reliable results, more extensive test sets are required, especially in the early stages of the disease. At the onset of the disease, a neurological examination usually shows nothing unusual, with the exception of obvious cognitive abnormalities that may resemble ordinary dementia. Therefore, for the differential diagnosis of Alzheimer’s disease and other diseases, an extended neurological examination is important. Interviews with family members are also used in assessing the course of the disease, since relatives can provide important information about the level of a person’s daily activity and about a gradual decrease in his mental abilities. Since the patient himself usually does not notice the violations, the point of view of the people caring for him is especially important. 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. Additional tests enrich the picture with information about some aspects of the disease or allow to exclude other diagnoses. A blood test can reveal alternative causes of dementia, which occasionally even respond to therapy that reverses the symptoms. Psychological tests are also used to detect depression, which can either accompany Alzheimer’s disease or cause cognitive decline.

Equipment SPECT- and PET-visualization with its availability can be used to confirm the diagnosis together with other assessment methods, including the analysis of mental status. In people who already suffer from dementia, SPECT, according to some sources, makes it possible to more effectively differentiate Alzheimer’s disease from other causes, as compared with standard testing and anamnesis. The ability to observe beta-amyloid deposits in the brain of living people was created by the creation of the Pittsburgh compound B (PiB) at Pittsburgh University, which binds to amyloid deposits when introduced into the body. The short-lived radioactive isotope carbon-11 in the compound allows you to determine the distribution of this substance in the body and obtain a picture of amyloid deposits in the patient’s brain using a PET scanner. It was also shown that the content of beta-amyloid or tau protein in the cerebrospinal fluid can be an objective marker of the disease. These two new methods led to proposals for the development of new diagnostic criteria.

Alzheimer’s Disease Treatment

Alzheimer’s disease cannot be cured; available therapies can have a small effect on the symptoms, but are inherently palliative. From the whole complex of measures, pharmacological, psychosocial and patient care measures can be distinguished.

Pharmacotherapy
Regulatory agencies such as the FDA and EMEA have now approved four drugs for the treatment of cognitive impairment in Alzheimer’s disease — three cholinesterase inhibitors and memantine, an NMDA antagonist. At the same time there are no such drugs, among the actions of which it would be indicated to slow down or stop the development of Alzheimer’s disease.

A known sign of Alzheimer’s disease is a decrease in the activity of cholinergic neurons. Cholinesterase inhibitors decrease the rate of acetylcholine (ACh) destruction, increasing its concentration in the brain and compensating for the loss of ACh caused by the loss of cholinergic neurons. As of 2008, doctors used such ACh-inhibitors as donepezil, galantamine, and rivastigmine (in the form of tablets and patches). There is evidence of the effectiveness of these drugs in the initial and moderate stages, as well as some reasons for their use at a later stage. Only donepezil is approved for use in severe dementia. The use of these drugs for mild cognitive impairment has not delayed the onset of Alzheimer’s disease. Among the side effects of drugs, the most common are nausea and vomiting associated with an excess of cholinergic activity, they occur in 10-10% of patients and may be mild or moderately expressed. Less common muscle spasms, bradycardia, loss of appetite, weight loss, increase in acidity of gastric juice.

The 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 noted not only in Alzheimer’s disease, but also in other conditions, such as Parkinson’s disease and multiple sclerosis. A drug called memantine, originally used in the treatment of influenza, inhibits the activation of glutamate NMDA receptors. The moderate efficacy of memantine in moderate and severe Alzheimer’s disease has been shown, but it is unknown how it acts at an early stage. Rarely observed mild side effects, among them – hallucinations, confusion, dizziness, headache and fatigue. In combination with donepezil, memantine demonstrates a “statistically significant, but clinically barely noticeable efficacy” in acting on cognitive performance.
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 impairment and reduced cognitive abilities, which precludes their daily use. With the prolonged prescription of antipsychotics for Alzheimer’s disease, increased mortality is noted.

Psychosocial intervention
“Sensory Integrative Therapy”: a special sensory room (eng. Snoezelen) is used for emotionally-oriented care for people suffering from dementia.

Psychosocial intervention complements the pharmacological and can be divided into the following approaches:

  • behavioral;
  • emotional;
  • cognitive;
  • stimulatory-oriented.

The effectiveness of the intervention has not yet been covered in the scientific literature; moreover, the approach itself does not extend to Alzheimer’s disease, but to dementia as a whole.

Behavioral intervention is aimed at identifying the prerequisites and consequences of problem behavior and working to correct them. When using this approach, there is no improvement in the overall level of functioning, but it is possible to alleviate some of the individual problems, such as incontinence. Regarding the effect of the techniques of this direction on other behavioral deviations, such as wandering, there is not enough qualitative data accumulated.

Interventions that affect the emotional sphere include memory therapy (reminiscence therapy, RT), validation therapy, supportive psychotherapy, sensory integration (“snoozelen”), and “simulated presence therapy” (SPT). Supportive psychotherapy has almost not been studied by scientific methods, but some clinical workers believe that it provides benefits when trying to help patients with ill health adapt to the disease. In memory therapy (RT), patients discuss their experiences face to face with the 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 on the effectiveness of RT is small, a positive effect of this method on the patient’s thinking and attitude is possible. Presence simulation based on attachment theories involves playing back audio recordings with the voices of the next of kin. According to preliminary data, patients undergoing a course of SPT, decreases the level of anxiety, the behavior becomes calmer. Validation therapy is based on the recognition of the reality and personal truth of the experiences of another person, and during sensory integration sessions the patient performs exercises designed to stimulate the senses. There is little data to support these two methods.

Orientation in reality, cognitive retraining and other cognitive-oriented therapies are used to reduce the cognitive deficit. 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 exertion. Some improvement in cognitive abilities was noted with the use of both the first and second methods, but in some studies this effect disappeared with time and negative manifestations were noted, for example, patient frustration.

Stimulating therapies include art therapy, music therapy, as well as types of therapy in which patients communicate with animals, exercise, and any other restorative activity. Stimulation, according to research, has a moderate effect on behavior and mood, and even less on the level of functioning. Be that as it may, such therapy is carried out mainly to improve the daily lives of patients.

Prevention of Alzheimer’s Disease

Intellectual activity, including the fascination with the game of chess, and regular communication correlate with a reduced risk of developing Alzheimer’s disease, according to epidemiological studies, however, a causal link has not yet been proven.

International studies designed to assess how this or that measure can slow down or prevent the onset of the disease often give conflicting results. To date, there is no solid evidence of the preventive effect of any of the factors considered. At the same time, epidemiological studies suggest that some corrective factors — diet, cardiovascular risk, medication, mental activity, and others — are associated with the likelihood of developing the disease. However, real evidence of their ability to prevent illness can be obtained only in the course of additional study, which will include clinical studies.

Ingredients of the Mediterranean diet, including fruits and vegetables, bread, wheat and other cereals, olive oil, fish and red wine, may, individually or together, reduce the risk and alleviate the course of Alzheimer’s disease. Acceptance of some vitamins, including B12, B3, C and folic acid, has been associated with a reduced risk of developing the disease in some studies, but other studies indicate the absence of a significant effect on the onset and course of the disease and the likelihood of side effects. Curcumin, which is contained in a common spice, when tested in mice showed some ability to prevent certain pathological changes in the brain.

Risk factors for cardiovascular diseases, such as high cholesterol and hypertension, diabetes, smoking, are associated with an increased risk and more severe course of Alzheimer’s disease, but cholesterol-lowering drugs (statins) have not been effective in preventing it or improving the condition of patients. The long-term use of nonsteroidal anti-inflammatory drugs is associated with a reduced likelihood of developing the disease in some people. Other medications, such as hormone replacement therapy in women, are no longer considered effective in preventing dementia. A systematic review of ginkgo biloba, conducted in 2007, indicates the inconsistent and inconclusive nature of the evidence on the effects of the drug on cognitive impairment, and another study suggests that there is no effect on the incidence.

Intellectual exercises, such as reading, board games, solving crossword puzzles, playing musical instruments, regular communication, may possibly slow the onset of the disease or mitigate its development. Bilingual knowledge is associated with a later onset of Alzheimer’s disease.
Some studies suggest an increased risk of Alzheimer’s disease in those people whose work involves exposure to magnetic fields, ingestion of metals, especially aluminum, or the use of solvents. Some of these publications have been criticized for their poor quality of work; moreover, other studies have not found a link between environmental factors and the development of Alzheimer’s disease.

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