The Alzheimer’s Disease is a progressive dementia disorder of the brain, which occurs mainly in old age and a progressive decrease in brain function is observed. The disease begins with small, apparently random forgetfulness and ends in the loss of reason. It is a disease of old age and rarely occurs before the 60th Year of life.

Auguste D.

For the first time the disease was found in 1906 by the physician Alois Alzheimer on Auguste D. The patient is diagnosed as an illness and organic, not psychological origin described, irrespective of approximately the same time by Oskar Fischer at the psychiatric clinic in Prague. The psychiatrist Emil Kraepelin named the disorder in his textbook of psychiatry from 1911, after Alois Alzheimer.

It comes to the degeneration of certain neurons and thereby contributes to disruption of normal cerebral functions, which leads with disorders in-patients in language, thinking and memory. The brain mass is in the course of the disease; one speaks of a cerebral atrophy. As a trigger of cell loss are currently being primarily intracellular deposits of a fragment of APP (amyloid precursor protein) are discussed. In addition, important neurotransmitters, including acetylcholine, no longer are produced in sufficient quantities, which leads to a general weakening of brainpower.

Causes

There is a genetic component in the causation of Alzheimer’s disease. Approximately five to ten percent of the subjects show a family history (FAD, familiar alzheimer disease) due to mutations in the presenilin 1 gene on chromosome 14, the presenilin 2 gene on chromosome 1 or mutation of the APP gene on chromosome 21. In addition, a link between the disease and Alzheimerischen the ε4 allele of apolipoprotein E (ApoE), one on cholesterol transport protein involved is produced.

The Down’s Syndrome, with its triple investment of genetic material of chromosome 21, on which the APP gene is located, also increases the risk of Alzheimer’s disease to cancer, but the evidence in people with this genome mutation usually present with a cognitive impairment difficult.

Moreover, a mutant variant of the gene SORL1 as increased risk factor for this disease.

Symptoms and disease course

Initial symptoms include forgetfulness, disorientation, resulting, first in their new surroundings, then also in their own home environment. In later stages of the disease reinforce these symptoms, so that the patient will always loose orientation. This is often a language disorder (word finding fault or wrong choice of words), then the patient can not recognize the names of his relatives or no longer call it. There will be disruptions in the emotional control, to drive reduction and thus to modify the social behavior and lead to severe coordination disorders at simple tasks (apraxia). Other hand, the patients sometimes agitation, are beginning to be moving furniture, etc. Another symptom is the belief bestohlen defendant. This symptom often occurs in the early stages.

In addition, it may be in advanced stages of Alzheimer’s as well as in other dementia disorders occasionally happen that the patient herself “rejuvenated.” He takes this all in his childhood and youth memories to determine its current perception of reality. Along with massive nightmares are nocturnal cries after the close, mostly deceased caregivers, such as the mother, not uncommon.

Diagnosis

Specific tests for the assessment of memory may reflect Alzheimer’s disease. There is an important role of the observations of relatives’ i.e. so-called external history. For other diseases, particularly other neuro-degenerative diseases are bloods and Liquoruntersuchungen and so-called imaging procedures such as computed tomography or magnetic resonance imaging are applied. In addition, you can use a positron emission tomography with fluorine-18-labeled sugar molecules may provide a reduction in the activity of the brain glucose turnover proof. In the parietal and frontal lobe area you will find significant differences comparable to normal populations.

The diagnosis of Alzheimer’s disease arises from the typical neuropathological findings, the course of the disease, the exclusion of other diseases, and possibly typical findings in imaging techniques. It is an exclusionary diagnosis; there are over 90% of the cases so diagnosed. A definitive diagnosis of Alzheimer’s disease is possible, but only after the death of the patient by means of a histological examination of the brain.

Abundance

As the proportion of elderly in the population of Western industrialized nations increases, the frequency of persons with Alzheimer’s also increases. It is estimated that about 2% of 65-year-olds are affected. The 3% of 70-year-olds are already in and the 6% 75-year-olds and in the 85-year-olds about 20% show symptoms of the disease. In the over 85-year-olds, because the previously ill the proportion of those rarely achieves is low. In Some parts of the world, currently more than 900,000 people are suffering from under a dementing disease, 650,000 of them in Alzheimer’s disease. Every year approximately 200,000 new diagnosed with dementia, of whom about 120,000 are from dementia Alzheimer type.

Prevention and risk factors

Many preventive measures against the typical diseases of civilization seem to reduce the likelihood of Alzheimer’s disease. For example, adequate physical activity, healthy diet with a high proportion of secondary plants substances such as the antioxidant quercetin, and unsaturated fatty acids and the lack of nicotine. A high level of education seems as favorable as lifelong mentally demanding activities. On the other hand frequent consumption of television is suspected to increase the Alzheimer’s risk. Hypertension is essential in early stage to reduce and may be strictly to minimize the risk of dementia, including the Alzheimer’s type.

These are but only more or less reasonable assumptions. It must be said restrictive: There are many observational studies, but few randomized-controlled, the efficacy of prevention evidence. Until today (2006) was in accordance with these strict study criteria for blood pressure control, a significant decrease of the probability observed in Alzheimer’s disease. Also demonstrated a lack of preventive medicine today.

Therapy

Currently there are treatment approaches with acetylcholinesterase inhibitors that decrease the degradation of acetylcholine. An example of a substance of this group is Rivastigmin. The aim of acetylcholine levels in the synaptic gap increases and the progression of the disease slowed. However, the study location to the effectiveness of these Alzheimer’s drugs remain contradictory. Sun provided a methodological weakness review of studies for the approval of these drugs has been significant. Also, the drugs obtained by the only minimal effect.

Another mechanism of action, the effect of the neurotransmitters glutamate, the most common excitatory chemical messenger in the central nervous system of learning and memory functions is involved, was in Europe in 2002 and in the USA 2003. The date, the only representative of this class is Memantine. Memantine is an NMDA (N-methyl-D-aspartate)-receptor antagonist and is intended by the manufacturer of the Alzheimer’s dementia disturbed glutamaterge normalize signal transduction. Study results show that Memantine for moderate leads to severe disease after six months for an overall slight improvement in cognitive disorders and disturbed Alltagsaktiviäten.

Furthermore, other symptoms in the course of the disease may occur, such as restlessness, depressed mood or arousal and aggression, with the help of certain psychotropic drugs treated. A cure is not possible.

New developments include the biology section of the German Society of Gerontology and Geriatrics Association and the German Alzheimer Society, whose main objective is to stabilize the supply and maintenance is borne environment.

Molecular Biology and Genetics

The deposits in the brain of an Alzheimer’s patients are senile plaques and fibrillar deposits. The protein deposits of senile plaques consist primarily of the amyloid β-peptide. The intracellularly located in Neurofibrillenbündel consist of tau protein. The tau protein aggregates to fibrils, when it is phosphorylated more than normal, i.e., with phosphoric acid remains is busy – it speaks of Hyperphosphorylierung. It is unclear whether this tau phosphorylation or secondary is disease.

The amyloid β-peptide, also known as Abeta or Aβ described arises from a precursor protein, the amyloid precursor protein (APP); a protein in the cell is inserted. The largest proportion of this protein protrudes from the cell, while only a small proportion within the cell (intracellular). It is a type I transmembrane protein, i.e. its amino-terminus is located on the cell exterior, while its carboxyl-terminus can be found within the cell.

Processing of amyloid precursor protein

APP is the protein-cleaving enzymes, called secretases split, leading to the release of the β-peptide from the precursor protein may occur. There are basically two ways in which APP can be divided.

1. The non-amyloidogene way: APP is an α-secretase cut. This cut will take place within that part instead of APP, which contains Aβ. This will prevent the formation of Aβ. It comes to the release of a large extracellular portion, whose function is not definitively clarified.
2. The way amyloidogene: APP is first of β-secretase cut and subsequently by γ-secretase. This cut, within the transmembrane domain is carried out, leads to the release of Aβ.

Both processes can take place in nerve cells be parallel. By β-and γ-secretase-formed Aβ peptides vary in length. The main type Aβ-40 is 40, while a small proportion, Aβ-42, 42 amino acids long. The length of the Aβ is central pathological importance, since the longer Aβ-42 a much higher tendency to aggregation aufweist, smaller than the Aβ-40.

Candidates for the α-secretase, the proteases ADAM 10 and ADAM17 and the β-secretase BACE1. The γ-secretase consists of a high molecular weight complex of the protein presenilin 1 and 2, PEN-2, and APH-1 and Nicastrin, which is not clear whether other proteins are involved.

New Developments

* The U.S. pharmaceutical company Myriad is expected in 2007 a new Aβ-42 lowering agent with the name of Flurizan on the market. Right now the authorization in the U.S. in Phase 3.

* U.S. researchers have achieved in animal experiments that early brain lesions of Alzheimer’s disease and reverse the progression of the disease to stop. Your report has been published in the journal Neuron (43/2004, p. 321-332) in August 2004.

* In mice had a kind of Alzheimer’s vaccine has already succeeded, told the Munich psychiatry professor Hans-Jürgen Möller in November 2004 to dpa. That would stimulate the body’s own defenses, so that the specific protein fragments “auffrisst”, which would otherwise form deposits in the brain and thus trigger the dementia.

* At the same time, clinical researchers are working on new drugs to prevent, the emergence of the fragments from the outset. “These drugs could be in five to ten years on the market,” said the director of the Clinic for Psychiatry and Psychotherapy of the Ludwig-Maximilians University in Munich.

* The proposal by the team led by Tobias Hartmann of the University of Heidelberg that Aβ-40 and Aβ-42 two different biological control loops, potentially opening up new opportunities for Alzheimer’s therapy. Wanted is now a substance that one is able, the amount of Aβ-40 to increase in order to reduce cholesterol levels, and also the quantity of Aβ-42 to reduce so that it does not come to the disease outbreak. As a further possibility of preventing Alzheimer’s, a general lowering cholesterol and the new rational justification for the relationship between cholesterol and Alzheimer’s approach enhances the existing core trials with cholesterol (statins).

* A recent American study showed that persons who are between their 20th and 50 Life year, a little mentally demanding activity have frequently Alzheimer’s disease. Possible explanations could be:

1. Mentally demanding activity will delay the disease or protect against the disease, for example, because the threshold at which Alzheimer’s starts to become annoying, hinaufgesetzt (this is the recognized state of scientific knowledge) BBC News August 2004; or
2. The disease breaks down already at the youth and prevents the inclusion of an intellectually challenging activity. The currently known Alzheimer’s symptoms are only seen in old age. An earlier study Neurology 2002; 59:887-893 affirmed by the second option, because low income in the later years of life has a connection with dementia, but low incomes in the middle years of life, not. This would mean that the disease itself during the professional life act (see “Frequency” above).

* You may go to Alzheimer’s disease associated with copper deficiency. Experiments with transonic mice have clearly shown that in mice with amyloid plaques of the copper mirror opposite absence very healthy animals. Test results from Alzheimer’s patients suggests that the metabolism of the essential metal copper Lions in Alzheimer’s disease be disturbed. In vitro studies came to light that an elevated AssPP (amyloid precursor protein) and Ace-mirror to decrease the copper levels leads.

* Due to the increased removal of copper from the cells creates a deficiency in the tissue, the cells in a reduced activity of the enzyme superoxide dismutase causes. Gerd Multhaup, Thomas Bayer of the Free University of Berlin, its volunteers administered Bioactive copper (through diet) and their suspicions were called in ADAS-cog test is confirmed. Currently at the University of the Saarland in the local Department of Psychiatry, headed by Frank Thomas Bayer Pajonk and a double-blind study with copper gifts, which are already in clinical phase II is 1, 2

* Since some time in the scientific literature of the influence of fehlgefalteten or biologically inactive metalloproteins (eg Kupferchaperon for Superoxiddismutase) associated with dementia are discussed. In a recent article describes how analytical methods (eg quantitative preparative native continuous polyacrylamide gel = QPNC-PAGE and NMR spectroscopy) Structure-function relationships of native and denatured metalloproteins in biological fluids can be elucidated.