The disease of Alzheimer is a neurodégénérative Maladie cerebral fabric which involves the loss progressive and irreversible functions Mental are. It is the leading cause of Démence at the Elderly, concerning approximately 24 million patients throughout the world.

The neurodégénératif process responsible for the disease is still badly known: it would be due to the formation of starch plates which start an inflammatory answer and/or to the appearance of tangles neurofibrillaires in the cellular bodies . The neuronal Atrophy resulting key initially at a stage Infraclinique the temporal Lobe (and in particular the hippocampus) then the associative cortices frontal and temporo-parietal at a Clinical stage .

The precise cause is still unknown, but it is supposed that factors Environnement with and Génétique S contribute to it. changes in at least four Gène S predisposing with the disease of Alzheimer were identified. They are particularly causes some in the family cases at early beginning. For the more common form of Alzheimer, several genes of susceptibility were identified.

Until in the Years 1960, one supposed that the disease was rare, but later one realized that in much case, which one had taken for normal aspects of the Sénescence concerned in fact this disease.

The striking primary symptom is the loss of the to remember the recent events (Amnésie); it appears initially by minor distractions which are accentuated gradually with the progression of the disease, while the older memories are relatively preserved. Thereafter, the deficits Cognitif S extend to the fields from the Langage (Aphasie), of the organization of the movements (Apraxie), of the visual recognition (Agnosie) and of the executive Fonctions (such as the Decision making and the Planification). These last symptoms reflect in particular the pathological process of degeneration reaching the frontal lobes Cerveau. These changes Psychological S influential on essential human qualities and for this reason the disease of Alzheimer is sometimes described as a disease where the victims undergo the loss of qualities which form the gasoline human Existence.

History

Aloïs Alzheimer (1864 - 1915) is a doctor psychiatrist and a German neuropathologist of the beginning of the 20th century which studied the brain of the people reached of Démence, thanks to a novel method of coloring with the Aniline and impregnations silver.

In 1906, Aloïs Alzheimer described for the first time the anatomical deteriorations observed on the brain of a 51 year old patient, Auguste D. Atteinte of insanity, it also presented Hallucination S and disorders of the orientation. In 1911, Alzheimer discovered a case identical to that of Auguste D.

It is the psychiatrist Emil Kraepelin who proposed that the disease bears the name of Alzheimer, of the name of his discoverer.

Epidemiology

One distinguishes usually a form " sporadique" , by far most common at the elderly, and a " form familiale" , beginning more precociously.

The disease of Alzheimer explains more half of the cases of insanity of the elderly. The incidence strongly increases with the age.

In Belgium, the prevalence of this insanity is estimated at 5 with 10  % after 65 years and with close to 20  % beyond 80 years.

In France, study “PAQUID” (1988-2001) emphasized that 17,8% of the people of more than 75 years are reached disease of Alzheimer or a related disease. According to the evaluations of 2004 approximately 860.000 people would be touched by the disease of Alzheimer or disorders connected in France. A figure which could reach 1,3 million in 2020 and 2,1 million in 2040. The number of new cases is approximately 225.000 per annum.

This disease seems more frequent if there exists a concept of cranial traumatism or vascular disease. This increased frequency can be however simply explained by an increased destruction of the neurons making more visible (or earlier) the disease.

Clinical aspects

The disease of Alzheimer usually begin with disorders from the memory. Others turbid cognitive appear gradually, leading to a table of Démence.

Anatomo-pathology

The brain of the patient reached of the disease of Alzheimer presents three types of lesions:

Senile plates (or plates starch)

They are extracellular lesions of the disease of Alzheimer. These plates correspond to an accumulation of a abnormal Peptide, beta-starch peptide consisted of 32 to 44 amino-acid . This peptide comes from a bad cleavage of protein APP (Amyloïd Protein Precursor). This would take part in the massive calcium entry in the neuron and would activate the microglie (inflammatory reaction), which results in the inescapable death of the neuron by necroses or apotose. These plates are essentiellements localized in the neocortex and the hippocampus.

Decays neurofibrillaires

They are secondary cellular lesions to the accumulation of the protein tau (protein of association to the microtubules which belong to the cytosquelette) hyperphosphorylée or abnormally phosphorylée, person in charge of the formation of filaments paired in pair. When the protein tau is hyperphosphorylée, it will be placed in the shape of pair of helicoid filaments. Being determining in the structure of the axon, this last will be rolled up around itself. The substances necessary to the good performance of the neuron could not thus be conveyed to the cellular body any more and the neuron will die.

A neurodégénérescence

With final, one can observe a degeneration of the neurons of the cerebral cortex (a loss of number) for example to the standard scanner or PET-SCAN via use of a tracer of glucose.

Etiology

Genetic of the disease of Alzheimer

Genetic forms

Less than 1% of the patients present a disease of purely genetic Alzheimer of origin. This form is characterized by:

Two genes are implied:

  • a change of the gene APP located on the chromosome 21 which codes a precursor of the protein Amyloïde (five changes of the codon 717 are known);
  • a change of the gene PSEN1 located on the chromosome 14 (many changes which are changes misinterpretation).

Genetic predispositions

The forms known as sporadic, i.e. nonfamily, also comprise a genetic predisposition:
  • it is the existence, discovered in 1993, of APOE4 is the Allèle 4 of gene of the apolipoprotéine E which is significantly related to an increase in risk of the disease of Alzheimer. But the presence of APOE4 is neither necessary nor sufficient to develop pathology;
  • the gene of the apolipoprotéine E is present in three allelic forms: the APOE2, APOE3, and APOE4. The first meets in 5% of the population, the second meets in 80% of the population and the third meets in 15% of the population;
  • the presence of APOE4 in the form Hétérozygote increases by 2 the disease risk of Alzheimer;
  • the presence of APOE4 in the form Homozygote increases by 11 the disease risk of Alzheimer.

This apolipoprotéine E would intervene in the mechanisms of neuronal repair.

Cellular mechanisms at the base of the neuronal degeneration

There exist two levels of mechanisms: intra- and extracellular.
Dans the two levels, there is a accumulation of proteins which involves a dysfunction of the cell. In the intracellular mechanisms, this accumulation is called Neurofibrille S. In the extracellular mechanisms, it is called starch plates.

Intracellular medium

In the microtubules, the Tau proteins is placed in a perpendicular way and allow the rigidity of the microtubules for transport axonal.

From time to time, at a normal subject, the Tau proteins are detached. They are replaced and thus degraded quickly.
Mais at a subject reached of disease of Alzheimer, the Tau proteins are detached from the microtubules, and fall into the intracellular medium. They all are not degraded and thus will be incorporated. It is that which will form the Neurofibrille S. the too important neurofibrilles block the operation of the Neuron and do not allow good axonal transport. The neurofibrilles compress the neuron and cause a neuronal death.

There exist two explanations to the detachment of the Tau proteins:

  • the Phosphorylation: it is what allows the functionality of protein. The Tau protein is very little phosphoryl and when it is very phosphorylée, it cannot stick to the microtubules. In fact thus the proteins are detached and accumulates by forming neurofibrilles. In this explanation, the cause of the increase in phosphorylation is unknown.
  • genetic factors: as for all proteins, there exists a gene which codes Tau protein. The gene can have seven different alleles. These seven alleles can be classified in two categories:
    • those with three reasons R,
    • those with four reasons R.
The Tau proteins which come from the alleles with three reasons R have a fixing less important than the proteins which come from the alleles with four reasons.

Extracellular medium

In the extracellular Medium, the concerned protein is the starch protein. It is a membrane protein (located on the membrane of the cell). This protein is detached from the membrane, and enters the extracellular medium. It is then recovered then degraded.

Among patients reached of the disease of Alzheimer, this degradation is not total and a fragment, called β-starch, remains and cannot be degraded. These fragments end by being incorporated and forming starch plates. While accumulating in the extracellular medium, these plates compress the Neuron S. It is this phenomenon which involves a dysfunction, which can be followed neuronal death.

Moreover, these senile plates will release a peroxide of formula H2O2. The connection between the two oxygen atoms being very weak, it goes quickly " casser" one will then obtain two molecules OH, called radical free . The free radicals do not comply with the rule of the byte, they are thus unstable. They will seek has to couple their free electron. To be done, they will tear off an atom of hydrogen to the membrane of the neuron (made up of molecules of CH4). The membrane " trouée" thus will let penetrate of other free radicals which will attack the DNA of the neuron.

The cause of accumulation also appears with normal ageing, but accumulation at the base of Alzheimer is little known.

The only factor is a genetic factor. That relates to another protein which would act with this formation process of the starch plates. It is called the apolipoprotéine E. this protein depends on an allele which can be of three kinds: E2, E3 and E4.
Les alleles E2 and E3 is specific mankind. They come from a change of the E4 gene. The most widespread Allèle is the allele E3 (70%), followed allele E4 (20%) then of the allele E2 (10%).
L' E4 allele is associated with the formation of the starch plates. This allele would allow the inhibition of the neuritic growth (formation of the Axone S and the dendrite S). This growth allows neuronal plasticity. This phenomenon is very important for the operation of the central Nervous system. The E4 allele is thus consequently associated with the diseases with the neuronal dysfunction. The E3 allele supports neuronal plasticity, but not as much as the E2 allele. For this reason the E2 allele is associated with longevity.

Appearance of the disease

To find how the disease appears, of the transgenic mice (genetically modified) are used. In certain mice, the gene coding the Tau protein is transferred. At others, it is the gene coding the starch protein which is transferred. Certain mice will undergo changes on two genes.

The mice, having had a change on gene coding the protein Tau, show an appearance of the not very marked disease. The mice, having had a change on gene coding starch protein, behave like healthy mice. The mice having sudden changes on two genes show an exacerbated disease, well defined.

That does not occur obligatorily in an identical way at the man, but that shows that the starch plates potentiate the appearance of the disease. The neurofibrilles appear initially and when the starch plates appear, the disease starts.

Diagnosis

The disease is presented in the form of disorders of the memory or the behavior, developing gradually towards a Démence. The cognitive disorders can be evaluated more finely by a standardized interrogation (form). Disorders of mood are associated frequently there. With a late phase a deterioration of the general state with dependence which can appears go until a denutrition, even the death.

The early detection of the disease of Alzheimer is a major element for a better treatment, and a better help of the patients and their friends.

The interest to detect the disease of Alzheimer precociously will be able to allow the future people reached to profit from possible futures treatments. According to a French research team, new criteria, coming from a combination between tests from memory, data of cerebral imagery and markers biological, could make it possible to detect the disease of Alzheimer at an early stage, as of the primary symptoms, “with a rate of certainty diagnoses higher than 90%”.

Risk factors

  • the age primarily (higher than 65 years),
  • of the family antecedents of disease of Alzheimer, or the existence of specific changes (préséniline, APP),
  • of the personal antecedents of depression, of cranial Traumatism, concept of exposure to the Aluminum (but these concepts are discussed),
  • the isoforme 4 of the apolipoprotéïne (seldom required),
  • a mode low in polyinsaturés fatty-acids omega-3 and rich in saturated fatty-acids.

Criteria of DSM-IV

These criteria rest on:

The installation of intellectual disorders carrying in a partial way or supplements on:

  • memory: Amnesia of the recent facts then old,
  • of the disorders of the executive Functions (i.e. of organization and realization of a complex task, such as for example filling its sheet with income tax return),
  • of the speech difficulties ( amnesic Aphasia ) characterized by " lapses of memory of the mot" ,
  • of the disorders of the praxie: Apraxia (i.e. of realization of complex gestures: for example to use the washing machine),
  • a Agnosia (turbid of recognition): for example of road panels, then of faces etc

These disorders are at the origin of a socio-professional repercussion.

Their evolution is done in a progressive and irreversible way (continuous decline…).

These signs are not explained by another cause: neither organics (tumoral, infectious, poison), nor psychic (depression, Schizophrenia), and apart from a acute confusion.

Tools for evaluation

The whole of these disorders (amnesia, disorders of the executive functions, aphasia, agnosia, apraxia) can be evaluated by a psychometric test: the ms (Mental Minis State Evaluation, or Test of Folstein), established on a scale of 30 points: a score lower than 24 out of 30 is suspect of insanity.
Ce result must however be interpreted according to the socio-economic level of the patient (an high level can improve the score and thus distort the test), just as it will be necessary to make sure of the absence of confusion before his realization.

A neuropsychological evaluation can be realized, evaluation which includes/understands many psychometric tests, among which:

  • in addition to one ms (Mental Minis State Evaluation or Test of Folstein),
  • a test known as of the clock (explores the praxie),
  • a test of recall (explores the memory).
as well as other explorations.

Complementary examinations

  • the cerebral scanner or IRM does not show specific lesions: the thinning of the cortex ( atrophies cortical or subcortical ) is seen in other diseases of the elderly. These examinations are primarily used to eliminate from other causes: Tumor S, Cerebral vascular accident, intracerebral Hématome or under-dural… Indices are however in the course of evaluation to try to make an early diagnosis (of which reduction in the size of the hippocampus).
  • the Tomographie with emission of positon S is a recent examination, allowing the analysis of certain radioactive tracers injected into the organization. One notes a rather clear reduction in the metabolism of several parts of the brain (temporal, parietal and posterior lobe) with a good sensitivity and specificity. The reduction in the activity of the hippocampus would be a promising index.
  • proportioning in the céphalo-rachidian Liquide of the protein T-tau shows that it is increased in the event of disease of Alzheimer, but this proportioning cannot be made yet in routine.
  • proportionings of the Vitamin B12 and the Vitamin B9 (folates), as well as a thyroid assessment (TSH) are systematically carried out, because a deficiency in vitamin B12 or B9 and a Hypothyroïdie can be the causes of insanity (curable insanity).

Diagnosis of Certainty

The only diagnosis of certainty of the disease of Alzheimer is the anatomo-pathological examination of the brain which can be carried out only after the death of the person reached.

In practice the diagnosis of probable disease of Alzheimer is done thus primarily at a person presenting of the signs of insanity of progressive appearance and for which the other causes were eliminated.

Differential diagnoses

  • at the initial stage of the disease, a benign Lapse of memory related to the age, a light cognitive Deficit or Mild cognitive impairment (MCI),
  • other forms of Insanity S of origin degenerative,
  • insanities known as secondary (with an organic disorder),
  • of the turbid anxious, a depression: from where interest of a treatment of test Anxiolytique and/or Antidepressant during a sufficient time; the persistence of the table will confirm that it is indeed an insanity.

If this assessment and this test of test are negative, it will be said that the diagnosis of disease of Alzheimer is probable ; the diagnosis could be certain only after a Autopsie with histological examination of the Cerveau. There does not exist diagnosis of certainty of the alive one.

Prevention

Researchers try to create a Vaccin which would prevent this insanity. This way of research remains promising.

Although there is not thus real method to be protected from the disease of Alzheimer, certain individuals are less inclined to develop the disease than others, and that is generally due to their past: the people having followed long studies would have had more time to develop their memory, and thus run less risks to suffer from the disease. A food rich in vitamins C and E would be also protective.

Now, to detect Alzheimer much earlier becomes possible. There is a program of artificial intelligence learned how to discriminate the signs heralding the benign cognitive disorders from those evolving to this disease with an error rate 7%.

It would be possible to divide by 2 the risk to develop the disease of Alzheimer by preserving a simple cognitive activity such as reading a newspaper, to play failures or with the ladies, to attend the bookstores, etc This reduction in risk is ascribable only with the current cognitive activities of the elderly. Those practiced in the past would not have any influence on the cognitive decline related to the age.

Treatment

Currently, there does not exist any treatment curing the disease of Alzheimer, nor even making it possible to stop its evolution, but there exist some medicamentous substances likely to delay the evolution of the disease. They make it possible to attenuate the losses of memory, the problems of language and reasoning, or quite simply to slow down at least seemingly the progression of the disease. These drugs are not permanent and are not always effective, which was at the origin of controversies relating in particular to their economic justification. Nevertheless, even the most severe organizations of expertise recognize their interest.

There exists another type of treatment, nonmedicamentous, namely a rehabilitation: certain courses allow the patient and his close relations of living with the daily newspaper with the disease, while others réhabituent the patient with living in an autonomous way. The occupational therapies, aiming at stimulating the attention of the patients, also have a certain effectiveness.

Symptomatic treatments

They modify in a nonspecific way the behavior of the patient without attacking the disease itself. Psychotrope S are employed to decrease the Angoisse, the Agressivité or the states of agitation of the patients. The Anticholinergic S, the Nerve sedative S and the Benzodiazépine S with long half-life are to be avoided because of their side effects among these very fragile patients.

Inhibiters of the acétylcholinestérase

As their name indicates it, they inhibit the degradation of the Acétylcholine, a molecule allowing the transmission between some Neuron S of the brain via its Synapse S.

Several inhibiters were tested and proved a certain effectiveness, at least in the light forms with moderately severe: the Donepezil, the Rivastigmine, and the Galantamine.

However, the effect of these treatments is stabilizing and they do not make it possible to cure the disease, nor to recover the preexistent performance level with its occurred. When a doctor decides to prescribe them, they must be introduced as soon as possible without awaiting advanced stages of the disease.

Antagonists of the NMDA

The neuronal receivers with N-methyl-D-ASPARTATe (NMDA) play a big role in the processes of memorizing. It seems that at the time of the disease of Alzheimer, these receivers are hyperstimulés what would be noxious. The Memantine is an inhibiter of the NMDA which was tested with contradictory results on the signs of the disease. It is reserved at the average or advanced stages.

Vaccine

The curative treatment of the disease of Alzheimer by a Vaccin would be possible, according to undertaken studies. The checkup of the vaccinated patients watch a statistical improvement their cognitive functions .

The idea is not new: in 1999, Flagstone Schenk, an American researcher, present in the review Nature a method to get rid of the disease at the Souris. While immunizing against the Peptide has beta of the mice Transgénique S which it surexpriment, it manages to prevent the appearance of deposits in the young animals and to limit and even reduce their extension at the old individuals.

A first Clinical trial of phase one at the man leads then in England is a success, the 80 treated patients support well vaccination and the quarter of them produces many antibody.

End 2001, of the clinical trials on 372 patients are launched (phase 2). Unfortunately the tests had to be stopped following cases of meningoencephalitis at 6% of the patients. The death of the one of the English patients allowed the Autopsie of sound Cerveau, only true means at present of determining the progress report of the disease. One discovered that certain starch deposits had disappeared from the cortical zones , as in the mice.

Other treatments

A certain number of drugs, tested for other diseases, were suspectés at one time or with another, to protect from the disease from Alzheimer. They are in particular certain Statine S, certain antioxydants (like the Vitamine E), some Anti-inflammatoire S. These studies observational, of which the initial goal was not that to treat the Démence, comprises many skews essentially and requires to be confirmed. The first results remain disappointing.

Genetic and demographic effects

Social consequences

a patient, it is a whole family which needs assistance. The family includes/understands the children, the brothers and sisters, nieces and nephews… While referring to the number currently estimated of 800.000 patients in France and considering an average of 3 family units around a patient, it is more than 2.400.000 people who are concerned more or less directly by the disease of Alzheimer . It is an main issue of company.

In the Western countries, the family has resources limited in time to offer to the sick person the support of which it progressively needs an increasingly continuous way of the evolution of the disease. However, in 70% of the cases, it is the family which deals with the sick person and allows him to remain in residence.

One became aware of the considerable contribution of these helping " naturels" and the professionals realize that l'" Helps with the aidants" is probably one in the manners of answering this enormous challenge of Public health.

Démographiquement, the category of age the most touched (80 years and more) is increasing. It is necessary for us thus to improve without delaying the system of the care offered to the people reached by the disease of Alzheimer, and especially to their close relations.

Information, formation, groups of mutual aid, possibilities of respite (receptions of day, or for given periods) are the principal means of allowing the close relations of ressourcer and of dealing with their task with effectiveness and humanity.

Others

September 21st is the “world day of the disease of Alzheimer” since 1993.

Famous patients reached of the disease of Alzheimer

Alzheimer with the cinema

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