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Recent Advance In The Treatment Of Alzheimer’s Disease

By: Mitul Shah | Views: 3844 | Date: 16-Jun-2010

Alzheimer's Disease (AD) is a neurodegenerative disease of the central nervous system associated with progressive memory loss resulting in dementia.

1) INTRODUCTION
Alzheimer's Disease (AD) is a neurodegenerative disease of the central nervous system associated with progressive memory loss resulting in dementia. 
Although each sufferer experiences Alzheimer's in a unique way, there are many common symptoms. The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most commonly recognized symptom is memory loss, such as difficulty in remembering recently learned facts. As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline. Gradually, bodily functions are lost, ultimately leading to death. Individual prognosis is difficult to assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming fully apparent, and it can progress undiagnosed for years. The mean life expectancy following diagnosis is approximately seven years. Fewer than three percent of individuals live more than fourteen years after diagnosis. (10)
The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain. Currently-used treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are as yet available. As of 2008, more than 500 clinical trials were investigating possible treatments for AD, but it is unknown if any of them will prove successful. Many measures have been suggested for the prevention of Alzheimer's disease, but their value is unproven in slowing the course and reducing the severity of the disease. Mental stimulation, exercise, and a balanced diet are often recommended, as both a possible prevention and a sensible way of managing the disease. 
Two pathological characteristics are observed in AD patients at autopsy: extracellular plaques and intracellular tangles in the hippocampus, cerebral cortex, and other areas of the brain essential for cognitive function. Plaques are formed mostly from the deposition of amyloid ß (Aß), a peptide derived from amyloid precursor protein (APP). Filamentous tangles are formed from paired helical filaments composed of neurofilament and hyperphosphorylated tau protein, a microtubule-associated protein. It is not clear, however, whether these two pathological changes are the markers or the causes of AD. Late-onset/sporadic AD has virtually identical pathology to early-onset/familial AD (FAD), thus suggesting common pathogenic pathways for both forms of AD. To date, genetic studies have revealed four genes that may be linked to autosomal dominant or familial early-onset AD (FAD).These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2), and apolipoprotein E (ApoE).    
All mutations associated with APP and PS proteins can lead to an increase in the production of Aß peptides, specifically the more amyloidogenic form, Aß42. In addition to genetic influences on amyloid plaque and intracellular tangle formation, environmental factors (e.g., cytokines, neurotoxins, etc.) may also play important roles in the development and progression of AD.
Dementia:  
It is an acquired, sustained impairment in intellectual function with Compromise in at least 3 of following spheres of mental activity. 
 Memory (amnesia)
 Language visuospatial skills
 Personality 
 Other instrumental cognitive abilities.

Amnesia: 
Amnesia is disorder of memory and refers to difficulty in learning new information. 
Some Statistics: 
 AD is most common cause of elderly dementia (70 % of dementia)
 3rd leading cause of death after heart disease and cancer.
 Incidence doubles every 5 Years.
 Average life span is 8-10 yrs after diagnosis. 
Because AD cannot be cured and is degenerative, management of patients is essential. The role of the main caregiver is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a great burden on caregivers; the pressures can be wide-ranging, involving social, psychological, physical, and economic elements of the caregiver's life. In developed countries, AD is one of the most economically costly diseases to society. 
Loss of cognitive ability with age is considered to be a normal process whose rate and extent is very variable. AD was originally defined as presenile dementia, but it now appears that the same pathology underlies the dementia irrespective of the age of onset. AD refers to dementia that does not have an antecedent cause, such as stroke, brain trauma or alcohol. Its prevalence rises sharply with age, from about 5% at 65 to 90% or more at 95. Until recently, age-related dementia was considered to result from the steady loss of neurons that normally goes on throughout life, possibly accelerated by a failing blood supply associated with atherosclerosis. Studies over the past three decades have, however, revealed specific genetic and molecular mechanisms underlying AD, which have opened potential new therapeutic opportunities.(11)

2) CLINICAL MANIFESTATION
The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment.
2.1) Predementia
These early symptoms can affect the most complex daily living activities. The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information. Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships), can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. 
2.2) Early dementia
In people with AD, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small proportion of them, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser degree than new facts or memories. Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead to a general impoverishment of oral and written language. As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities. 
2.3) Moderate dementia 
Progressive deterioration eventually hinders independence. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Common neuropsychiatric manifestations are wandering, sundowning, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Approximately 30% of patients also develop illusionary misidentifications and other delusional symptoms.Urinary incontinence can develop (15)
2.4) Advanced dementia
During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, patients can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results. Patients will ultimately not be able to perform even the simplest tasks without assistance.
3) PATHOGENESIS OF ALZHEIMER'S DISEASE  
3.1 Introduction 
Alzheimer's disease is associated with brain shrinkage and localised loss of neurons, mainly in the hippocampus and basal forebrain. The loss of cholinergic neurons in the hippocampus and frontal cortex is a feature of the disease, and is thought to underlie the cognitive deficit and loss of short-term memory that occur in AD. Two microscopic features are characteristic of the disease, namely extracellular amyloid plaques, consisting of amorphous extracellular deposits of β-amyloid protein (known as Aβ), and intraneuronal neurofibrillary tangles, comprising filaments of a phosphorylated form of a microtubule-associated protein (Tau). Both of these deposits are protein aggregates that result from misfolding of native proteins, as discussed above. 
They appear also in normal brains, although in smaller numbers. The early appearance of amyloid deposits presages the development of AD, although symptoms may not develop for many years. Altered processing of amyloid protein from its precursor (amyloid precursor protein, APP) is now recognised as the key to the pathogenesis of AD. This conclusion is based on several lines of evidence, particularly the genetic analysis of certain, relatively rare, types of familial AD, in which mutations of the APP gene, or of other genes that control amyloid processing, have been discovered. The APP gene resides on chromosome 21, which is duplicated in Down's syndrome, in which early AD-like dementia occurs in association with over expression of APP.
3.2) Amyloid plaque Formation
Amyloid Precursor Protein (APP) 
APP is an integral membrane protein, occurring in different isoforms. The common isoforms contain 695 (APP695), 751 (APP751) and 771 (APP771) amino acids, respectively. Among these isoforms, APP695 is the major isoform and is expressed exclusively in neurons .In contrast, APP751 and APP770 are expressed in both neural and non-neural cells. The primary structure of APP has a signal sequence, a large extramembranous N-terminal region, a single transmembrane domain, and a small 47 aa residue cytoplasmic C-terminal tail. The APP proteins mature in the endoplasmic reticulum and Golgi apparatus and exhibit post-translational modifications, including phosphorylation, glycosylation and  sulfation.(16)
Amyloid deposits consist of aggregates of Aβ containing 40 or 42 residues. Aβ40 is produced normally in small amounts, whereas Aβ42 is overproduced as a result of the genetic mutations. Both proteins aggregate to form amyloid plaques, but Aβ42 shows a stronger tendency than Aβ40 to do so, and appears to be the main culprit in amyloid formation. Aβ40 and 42 are produced by proteolytic cleavage of a much larger (770 amino acid) APP, a membrane protein normally expressed by many cells, including CNS neurons. It is a 42-Amino Acid Chain Produced by Cleavage of Larger Protein called Amyloid Precursor Protein (APP). The proteases that cut out the Aβ sequence are known as secretases. 
Normally, α;-secretase acts to release the large extracellular domain as soluble APP, which serves various poorly understood trophic functions. Formation of Aβ involves cleavage at two different points, including one in the intramembrane domain of APP, by β- and γ-secretases. γ-Secretase is a clumsy enzyme-actually a large intramembrane complex of several proteins-that lacks precision and cuts APP at different points in the transmembrane domain, generating Aβ fragments of different lengths, including Aβ40 and 42. Mutations in this region of the APP gene affect the preferred cleavage point, tending to favour formation of Aβ42. Mutations of the unrelated presenilin genes result in increased activity of γ-secretase, because the presenilin proteins form part of the γ-secretase complex. These different AD-related mutations increase the ratio of Aβ42:Aβ40, which can be detected in plasma, serving as a marker for familial AD. Mutations in another gene, that for the lipid transport protein ApoE4, also predispose to AD, probably because of expression of abnormal ApoE4 proteins that facilitate the aggregation of Aβ.

Fig.1 Processing of APP protein in brain
Three proteases, a-, ß- and γ secretases, are involved in APP cleavage. At the cell surface, APP undergoes proteolysis by an α-secretase that cleaves between Lys687 and Leu688 thus releasing a large, soluble ectodomain (α-APP). The C-terminal fragment (83 aa, ~10 kDa) is retained within the cell membrane. This fragment can then be cleaved by γ secretase at aa residues 711 or 713 within the APP transmembrane domain thereby releasing the p3 peptide. Alternatively, uncleaved cell surface APP can be internalized by endocytosis via coated vesicles in the distal cytoplasmic domain.
The full-length APP can then be trafficked to later endosomes and lysosomes for degradation or transferred to early endosomes for generation of Aß peptides. In the early endosomes, APP is cleaved by ß-secretase after Met671, creating a membrane-retained C-terminal fragment . Cleavage by ß-secretase exhibits relatively rigid primary sequence requirements (i.e., between Met671 and Asp672 of APP). At the membrane surface, the 12 kDa C-terminal fragment can then be further cleaved by γ -secretase within the hydrophobic transmembrane domain at either Val711 or Ile713 thus releasing an Aß peptide (i.e., either Aß40 and Aß42).
Identification and characterization of the ß- and γ secretases have been important areas of focus in AD research. Although several candidates have been suggested for ß-secretase, BACE is the only one identified having complete ß-secretase activity. Cloning and expression of the enzyme reveals that the human brain ß-secretase/BACE is a membrane-bound aspartic proteinase. The -secretase has not been definitively identified yet. Numerous studies, however, have linked  γ secretase and PS1 as either the same enzyme molecule or cofactors within the same complex.(19)
Presenilin-1 (PS1) and Presenilin-2 (PS2)
PS1 and PS2 are integral membrane proteins that contain multiple transmembrane domains. PS1 and PS2 have a similar predicted structure and share 67% aa identity. Both proteins are predominantly located within the endoplasmic reticulum (ER) and early Golgi apparatus .They are primarily expressed in neurons and are ubiquitously expressed within the brain. 

Fig. 2. PS1 (presenilin-1) plays a role in - γ secretase cleavage of APP (amyloid precursor protein).  
Endogenous PS1 and PS2 proteins are proteolytically cleaved to generate two polypeptides. The 46 kDa PS1 protein is cleaved to yield a 28 kDa N-terminal fragment (NTF) and an 18 kDa C-terminal fragment (CTF), whereas the 55 kDa PS2 protein is cleaved to yield a 35 kDa NTF and a 20 kDa CTF. The predominant species of both PS1 and PS2 observed in both cultured mammalian cells and the brain are the processed fragments. Full-length PS1 has been found only in transected cell lines and transgenic mice that over express PS1.                         
The exact functions associated with PS proteins have not been fully characterized yet.  PS1 is required for proper formation of the axial skeleton and is involved in normal neurogenesis and survival of progenitor cells and neurons in specific brain regions.PS proteins have also been proposed to function in the control of apoptosis. As mentioned previously, PS1 is also involved in γ secretase activity. Additionally, the binding of PS proteins to APP may play an important role in inducing intercellular signaling.
The majority of early onset FAD cases are caused by mutations within the PS genes. More than forty mutations have been described in the gene for PS1 that can subsequently result in FAD. Mutations in both PS1 and PS2 are associated with an increased production of the Aß42 peptide. Aß42, the more amyloidogenic form of Aß., can aggregate to form diffuse and neuritic amyloid plaques, thus suggesting that the influence of PS proteins on the production of Aß42 may be an initiating event for developing AD. Mutations in the PS1 gene may also facilitate neuronal apoptosis by destabilizing ß-catenin (i.e., part of the PS protein complex), thus predisposing individuals to early onset FAD.

Fig.3  Formation of Amyloid Plaque
It is uncertain exactly how Aβ accumulation causes neurodegeneration, and whether the damage is done by soluble Aβ monomers or oligomers,or by amyloid plaques. There is some evidence that the cells die by apoptosis, although an inflammatory response is also evident. Expression of Alzheimer mutations in transgenic animals causes plaque formation and neurodegeneration, and also increases the susceptibility of CNS neurons to other challenges, such as ischaemia, excitotoxicity and oxidative stress, and this increased vulnerability may be the cause of the progressive neurodegeneration in AD. These transgenic models will be of great value in testing potential drug therapies aimed at retarding the neurodegenerative process.

Fig.4. Astrocytes and microglial cells associated with Aß plaques can release a variety of cytokines and other factors. 
Aß itself can also stimulate cells associated with plaques to release cytokines, chemokines and reactive oxygen species (ROS). These cytokines can initiate a complex of interactions, such as upregulation of expression and processing of APP, induction of cytokine overexpression (i.e., autocrine and/or paracrine loops), and recruitment of immune cells, which may all lead to degeneration of specific neuronal populations within the AD-affected patient.
Proteolytic cleavage of APP results in generation of Aß peptides of various lengths. Ab peptides are normally soluble monomers that circulate at low levels in cerebrospinal fluid and blood. In the brains of AD patients, formation of insoluble, fibrillar plaques is facilitated by an increase and accumulation of Aß peptides. The predominant form of Aß peptides found within conditioned cell culture media and cerebrospinal fluid is the shorter Aß40 peptide. Aß42, however, is the Aß peptide form initially deposited within the extracellular plaques of AD patients. This may be explainedby the following. All FAD-linked mutations identified within APP lead to the increased production of Aß 42 Additionally; Aß42 tends to aggregate at a faster rate and at lower concentrations than the Aß40 form.
3.3) Tau Protein

Fig.5 Intracellular tangles found within neurons of brain regions essential for cognitive function are one of the pathological characteristics associated with AD.Filamentous tangles are formed from paired helical fragments (PHF) composed of neurofilament and hyperphosphorylated tau protein. Polymerization of hyperphosphorylated tau protein leads to PHF formation. PHF can also be modified by glycosylation and ubiquitination.
Axons use microtubules to transport substances between center of neuron and its outer portions.
Assembly and structural integrity of microtubules are dependent on several proteins, important is tau protein. 
The ability of tau protein to bind to microtubule segments is determined partly by the number of phosphate groups attached to it increased phosphorylation of tau protein may disturb this normal process and forms Helical filaments known as neurofibrillary tangles. 

The larger pyramidal neurons of the cortex and the forebrain (Ach neurons among others) that are important for cognition have more microtubule than other neurons and hence more tangles in Alzheimer’s disease, hence reduced cognitive ability. 
The other main player on the biochemical stage is tau, the protein of which the neurofibrillary tangles are composed.  Their role in neurodegeneration is unclear, although similar 'tauopathies' occur in many neurodegenerative conditions. Tau is a normal constituent of neurons, being associated with intracellular microtubules. In AD and other tauopathies, it becomes abnormally phosphorylated and is deposited intracellularly as paired helical filaments with a characteristic microscopic appearance. When the cells die, these filaments aggregate as extracellular neurofibrillary tangles. It is possible, but not proven, that tau phosphorylation is enhanced by the presence of Aβ plaques. Whether hyperphosphorylation and intracellular deposition of tau harms the cell is not certain, although it is known that tau phosphorylation impairs fast axonal transport, a process that depends on microtubules. 

3.4) Acetyl Choline Depletion :
 Most striking symptom (decreased by 90 %) which contributers for loss of memory and loss of attentiveness.
 Acetyl cholinesterase breaks down ach and ends the chemical signal.
 Neuronal degeneration weakens or destroys the correct signal modulation, so the correct neural message are unable to be delivered at the synapse, hence memory loss. 
3.5) Lipofuscin:
 Is an age pigment, accumulates in neurons and other cells as we age and may lead to neurodegeneration. 
3.6) Aluminium Toxicity:
 Thought to be a risk factor for development of beta amyloid plaques and Neurofibilary tangles, hence dementia in Alzheimer’s disease.
 Desferrioxamine a chelator of Al has been used in treatment of Alzheimer’s   disease.
3.7) Biopterin:
 Decreased in Alzheimer’s disease, decreases the synthesis of monoaminergic transmitters like dopamine, norepinephrine and serotonin.
 Administration of vitamin B12 and 5- Methyl tetrahydroxyfclate, precursors of tetrahydrobiopterin is beneficial in Alzheimer’s disease. 
3.8) Excitotoxicity:
 Is a Neuronal damage produced by disproportionate action of the excitatory neurotransmitter   glutamate?
 High   concentration   of glutamate cause an excessive elevation of calcium which leads to membrance damage and cell death.
4) Diagnosis:
Although a definite diagnosis of Alzheimer’s disease Require tissue examination at autopsy or Biopsy (After Death), the diagnosis can be made with high accuracy by applying specific clinical criteria.
Psychological findings like mini mental status exam , mattis dementia rating scale.
Clock drawing test:
EEG, traces brain wave activity, Alzheimer’s disease shows slow waves.
Imaging Tests like Ct. MRI, SPECT and PET later two can be used in early detection of alzheimer’s diesase.
Investigative tests like blood test fro Ach and other transmitters, CSF test for Beta amyloid, etc. 
5) Treatment of Alzheimer's Disease. 
Recent advances in understanding the process of neurodegeneration in AD have yet to result in therapies able to retard it. Currently, cholinesterase inhibitors and memantine are the only drugs approved for treating AD, although many drugs have been claimed to improve cognitive performance and several new approaches are being explored.  
5.1) Cholinesterase inhibitors  
Tacrine, the first drug approved for treating AD, was investigated on the basis that enhancement of cholinergic transmission might compensate for the cholinergic deficit. Trials showed modest improvements in tests of memory and cognition in about 40% of AD patients, but no improvement in other functional measures that affect quality of life. Tacrine has to be given four times daily and produces cholinergic side effects such as nausea and abdominal cramps, as well as hepatotoxicity in some patients, so it is far from an ideal drug. Later compounds, which also have limited efficacy but are more effective than tacrine in improving quality of life, include donepezil, rivastigmine and galantamine . These drugs produce a measurable, although slight, improvement of cognitive function in AD patients, but this may be too small to be significant in terms of everyday life.   
There is some evidence from laboratory studies that cholinesterase inhibitors may act somehow to reduce the formation or neurotoxicity of Aβ, and therefore retard the progression of AD as well as producing symptomatic benefit. Clinical trials, however, have shown only a small improvement in cognitive function, with no effect on disease progression.   
Other drugs aimed at improving cholinergic function that are being investigated include other cholinesterase inhibitors and a variety of muscarinic and nicotinic receptor agonists, none of which look promising on the basis of early clinical results. 
A somewhat more successful strategy has been the use of inhibitors of acetylcholinesterase (AChE), the catabolic enzyme for acetylcholinehysostigmine, a rapidly acting, reversible AChE inhibitor, produces improved responses in animal models of learning, and some studies have demonstrated mild transitory improvement in memory following physostigmine treatment in patients with AD. The use of physostigmine has been limited because of its short half-life and tendency to produce symptoms of systemic cholinergic excess at therapeutic doses. 
Four inhibitors of AChE currently are approved by the FDA for treatment of Alzheimer's disease: tacrine (1,2,3,4-tetrahydro-9-aminoacridine; COGNEX), donepezil (ARICEPT), rivastigmine (EXCELON), and galantamine (RAZADYNE). Tacrine is a potent centrally acting inhibitor of AChE. Studies of oral tacrine in combination with lecithin have confirmed that there is indeed an effect of tacrine on some measures of memory performance, but the magnitude of improvement observed with the combination of lecithin and tacrine is modest at best. The side effects of tacrine often are significant and dose-limiting; abdominal cramping, anorexia, nausea, vomiting, and diarrhea are observed in up to one-third of patients receiving therapeutic doses, and elevations of serum transaminases are observed in up to 50% of those treated. Because of significant side effects, tacrine is not used widely clinically. Donepezil is a selective inhibitor of AChE in the CNS with little effect on AChE in peripheral tissues. It produces modest improvements in cognitive scores in Alzheimer's disease patients and has a long half-life allowing once-daily dosing. Rivastigmine and galantamine are dosed twice daily and produce a similar degree of cognitive improvement. Adverse effects associated with donepezil, rivastigmine, and galantamine are similar in character but generally less frequent and less severe than those observed with tacrine; they include nausea, diarrhea, vomiting, and insomnia. Donepezil, rivastigmine, and galantamine are not associated with the hepatotoxicity that limits the use of tacrine.
Other drugs  
Dihydroergotamuine was used for many years to treat dementia. It acts as a cerebral vasodilator, but trials showed it to produce little if any cognitive improvement. 'Nootropic' drugs such as piracetam and aniracetam improve memory in animal tests, possibly by enhancing glutamate release, but are probably ineffective in AD.
5.2) Anti – Oxidants: 
Selegiline ( MOA Inhibitor), Tocopherol (Vitamin E) , Vitamin A and C. 
Ginkgo Biloba found modest improvement in cognitive function in  Subjects with Alzheimer’s Disease and Vascular Dementia.
N-Acetyl Cystein, A precursor for Glutathione..

5.3) Antidepressant Medication. :
Selective Serotonin Reuptake inhibitors (SSRIS) 
Tricyclic Antidepressants with Low Anticholinergic Side Effects (disipramine and Nortriptyline). Generalized Seizures treated with an Anticonvulsant, Such as Phenytoin or carbamazepine.
Agitation, Insomnia, Hallucinations, And Belligerence are Especially troublesome characteristics of some Alzheimer’s disease patients. Mild sedation with Benadryl may help Insomnia, and Agitation has been Variously treated with phenothiazines (Such as Thioridazine). Haloperidol, risperidone and Benzodiazepines (Such as Lorazepam). 
5.4) NMDA Glutamate receptor Antagonist
An alternative strategy for the treatment of AD is the use of the NMDA glutamate-receptor antagonist memantine (NAMENDA). Memantine produces a use-dependent blockade of NMDA receptors. In patients with moderate to severe AD, use of memantine is associated with a reduced rate of clinical deterioration. Whether this is due to a true disease-modifying effect, possibly reduced excitotoxicity, or is a symptomatic effect of the drug is unclear. Adverse effects of memantine usually are mild and reversible and may include headache or dizziness.
5.5) Recent Target for treatment of Alzheimer Disease 
5.5.1) Inhibiting neurodegeneration  
Now that we have several well-characterized targets, such as Aβ formation by the β- and γ-secretases, and Aβ neurotoxicity, together with a range of transgenic animal models of AD on which compounds can be tested, the prospects certainly look brighter than they did a decade ago. Particular developments are worth mentioning .
An ingenious new approach was taken by Schenk et al, who immunized AD transgenic mice with Aβ protein, and found that this not only prevented but also reversed plaque formation. Initial trials in humans had to be terminated because of neuroinflammatory complications, but work on developing better immunization strategies is continuing,
Aβ plaques bind copper and zinc, and removal of these metal ions promotes dissolution of the plaques. The amoebicidal drug clioquinol is a metal-chelating agent that causes regression of amyloid deposits in animal models of AD, and showed some benefit in initial clinical trials. Clioquinol itself has known toxic effects in humans, which preclude its routine clinical use, but less toxic metal-chelating agents are under investigation.
A major approach to the treatment of AD has involved attempts to augment the cholinergic function of the brain). An early approach was the use of precursors of acetylcholine synthesis, such as choline chloride and phosphatidyl choline (lecithin). Although these supplements generally are well tolerated, randomized trials have failed to demonstrate any clinically significant efficacy. 

5.5.1a) Alzheimer's vaccine
Several scientific teams at medical universities and pharmaceutical companies are working to develop a vaccine that can induce the body's own immune system to attack the amyloid plaques that build up in the brains of those with Alzheimer's disease. 
A number of different approaches to vaccine development are in the works. In one novel approach, scientists administered the vaccine to mice through the nose, rather than by injection. In that study, when young mice bred to have symptoms of Alzheimer's were repeatedly given the human amyloid via the nasal route, the mice had a much lower amyloid burden at middle age than animals not receiving the vaccine. Interest in the vaccine approach heightened upon recent preliminary reports that amyloid vaccination prevents cognitive decline in another mouse model of the disease, suggesting that a vaccine might indeed make a difference in the clinical symptoms of Alzheimer's. Preliminary studies in animals are now underway to test the safety and potential efficacy of these vaccines, which may one day be a valuable part of the armamentarium doctors employ to battle Alzheimer's. 
The key points of their findings were: 
159 patient/caregiver pairs took part in the follow-up (30 placebo patients and 129 patients on AN1792). Of the 129 AN1792 patients, 25 were classed "antibody responders". Compared to the placebo group, the antibody responders showed significant favourable results in: ability to look after themselves and pursue leisure activities; dependency on caregivers; and memory and thinking skills. 
After the first year, brain volume changes in antibody responders and placebo patients were similar. 
No further cases of encephalitis were observed. 
"The favorable results on Activities of Daily Living among the antibody responders in this study support the hypothesis that amyloid beta immunotherapy may have long-term benefits for patients with mild to moderate Alzheimer's and their caregivers," said Grundman.
5.5.1b) Anti-Amyloid: Alzhemed
Tramiprosate, brand name Alzhemed (made by Neurochem) is an orally-administered amyloid beta antagonist that is currently in Phase III clinical trials to assess its safety, efficacy and disease modifying effects in patients with mild to moderate Alzheimer's.
Alzhemed binds to amyloid beta protein and interferes with its ability to build plaque and poison brain cells.
Dr Paul Aisen, Professor of Neurology and Medicine, and Director of the Memory Disorders Program at the Georgetown University Medical Center, Washington DC , and lead author presented the conference with an update of the trial.
The key points were: 
The randomized, double-blind, placebo controlled trial enrolled 1,052 patients from several medical centres in the US and Canada. 
All patients were taking doses of acetylcholinesterase inhibitors, with or without memantine. Patients took either the active drug or a placebo twice a day for 18 months and were assessed every three months. Assessments included tests of cognitive function, disability, clinical efficacy, and volumetric MRI to assess effect of the disease on brain volume. Unfortunately Aisen was unable to present any conclusions because there is a lot of complex data that is still being processed. Apparently there are significant unexpected differences in the data coming from the various sites and these need to be accounted for before the results can be finalized (13)
5.5.1 c) Gamma (ץ) secration
Inhibitors of β- and γ-secretase have been identified and are undergoing clinical trials. Unfortunately, γ-secretase plays a role in other signalling pathways besides Aβ formation, so inhibitors are likely to produce unwanted as well as beneficial effects.
None of the treatments presently approved for Alzheimer's disease alter the progressive underlying disease processes. Early changes in the brain, including amyloid deposits and formation of neurofibrillary tangles, may play a causative role in AD. Interfering with these processes may be one way to treat or prevent the disease. One promising approach reported recently involves blocking the activity of enzymes (specialized proteins) involved in the formation of amyloid, offering a new target for drug development.
Amyloid is a small molecular fragment (peptide) produced as a result of snipping (cleavage) of the much larger amyloid precursor protein (APP) by two enzymes known as beta (ß) and gamma (γ) secretases. For years, scientists knew that something was snipping the APP into fragments and they even went so far as to name the suspect secretases. But no one had been able to physically and precisely identify the enzymes that did the actual clipping of APP until recently, when the identities of the beta and gamma secretases at last were revealed. 
The identity of beta secretive was discovered simultaneously by several drug companies. However, gamma secretase has proven more elusive. Its activity was known to be affected by mutations in one of the genes (presenilin 1, or PS1) that cause early-onset AD in families. PS1 was identified several years ago, and recent research strongly suggests that PS1 is itself the gamma secretase. It is believed this line of research could lead to the discovery of drugs that inhibit the production of amyloid without inhibiting other essential functions these secretase enzymes might have. Ultimately, clinical trials on such secretase-inhibiting drugs will show whether this approach will work.(22)
5.5.2) Estrogen Replacement Therapy. 
A few large studies have investigated whether taking estrogen replacement therapy may help slow the progression of Alzheimer's in women with the disease. 
So far, the largest and best-designed studies have found that estrogen does NOT have a beneficial effect on women who already have Alzheimer's. However, these studies do not answer the question of whether normally aging women who take estrogen after menopause will be protected from developing Alzheimer's or age-related cognitive decline.
The findings also showed that combination hormone replacement did not protect against a milder form of memory loss called mild cognitive impairment (MCI). MCI is characterized by memory lapses that can accompany aging and, in some cases, eventually lead to Alzheimer's.
It is also important to note that the possibility remains that estrogen-only replacement might afford protection against Alzheimer's, especially if administered at or around the onset of menopause rather than many years later. However, unopposed estrogen replacement is only available for women who have had hysterectomies. If these women are indeed found to have a diminished risk of Alzheimer's, that will fuel the search for brain-specific estrogen-like molecules that can protect the brain but spare the side effects on the reproductive tissues.
5.5.3) Anti-inflammatory Drugs.
One of the hallmarks of Alzheimer's disease is inflammation in the brain, but whether it is a cause or an effect of the disease is not yet known. Epidemiologic evidence strongly suggests that anti-inflammatory agents, such as prednisone (a steroid) and the popular pain relievers known as non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and indomethacin are associated with a decreased risk of Alzheimer's. Studies in animal models of Alzheimer's suggest that an NSAID can limit plaque production in the mouse brain.
Epidemiological studies reveal that some non-steroidal anti-inflammatory drugs (NSAIDs) used routinely to treat arthritis reduce the likelihood of developing AD. Ibuprofen and indomethacin have this effect, although other NSAIDs, such as aspirin, do not, nor do anti-inflammatory steroids such as prednisolone. Recent work  suggests that NSAIDs may reduce Aβ42 formation by regulating γ-secretase, an effect unrelated to cyclo-oxygenase inhibition, by which NSAIDs reduce inflammation. It may therefore be possible to find compounds that target γ-secretase selectively without inhibiting cyclo-oxygenase, thus avoiding the side effects associated with current NSAIDs. Disappointingly, clinical trials with various NSAIDs have so far failed to show any effect on cognitive performance or disease progression in AD patients .
There is evidence that these or related drugs can reduce the risk of developing the illness in the first place if given to people before the onset of symptoms. A large 2002 study that followed nearly 7,000 patients for an average of 6.8 years found that people who did not use NSAIDs had a nearly five times greater risk of developing the disease than those who used NSAIDs long-term (24 months or more of cumulative use). People who used NSAIDs for more than one but less than 24 months also had a decreased risk of developing Alzheimer's. The risk did not vary according to age. These data provide perhaps the most convincing evidence to date that NSAIDs may be useful in the prevention of Alzheimer's disease.
However, in late 2004, a large government study designed to test whether the anti-inflammatory drugs naproxen (an NSAID sold as Aleve) or Celebrex (a pain reliever related to Vioxx and known as a COX-2 inhibitor) was halted after researchers noted that these drugs may cause an increased risk of heart attacks and strokes. Researchers had long known that NSAIDs are associated with gastrointestinal problems, including bleeding ulcers and with kidney problems, but the heart complications present an additional potential danger. These drugs must be used with caution, and only under a doctor's supervision.
More research is needed on the safety of the various anti-inflammatory drugs and their possible benefits for treating or preventing Alzheimer's disease. It is possible that those with Alzheimer's who take different anti-inflammatories or different doses might show benefits. More studies of NSAIDs are under way. Drugs that work against toxic amyloid, the substance that contributes to plaque buildup and that is thought to be key to Alzheimer's, are also under investigation.(21)
5.5.4) Diabetes drug : Avandia  
Rosiglitazone, brand name Avandia (made by GlaxoSmithKline) is already approved for treatment of type 2 diabetes (but not for Alzheimer's). It lowers blood sugar by helping cells use insulin more effectively.
However, in recent months, Avandia has been in the spotlight because a recent study that reviewed the available published research suggested that diabetes patients on Avandia were at increased risk of heart attack and death from cardio vascular causes.
Researchers studied the effect of an extended release form of Avandia (Rosiglitazone XR) on Alzheimer's patients for 12 months. This was a follow up open lable extension to a randomized controlled trials. 
The results suggested that Avandia may help some Alzheimer's patients depending on their genetic make up. Patients that were "APOE e4 negative" did benefit from the treatment, they showed some improvement. But patients who were "APOE e4 positive" either did not improve or continued to decline.
Few patients had clinically significant changes in heart rate (less than 1 per cent) or abnormal ECG readings (2 per cent). 
Insulin and glycemic control measures were within the range expected for older people with low insulin resistance. 
Although there is controversy surrounding the use of Avandia as a type 2 diabetes drug because of the link with elevated heart problem risks, these risks could be outweighed by the potential benefits when considering the benefit-risk profile of person with Alzheimer's.
Global Clinical Vice President, Neurology, at GlaxoSmithKline, Dr Michael Gold said that Avandia appeared to have a safety profile similar to that already seen in diabetes type 2 patients. He added that :
"Rosiglitazone XR (Avandia) appeared to be generally well tolerated in subjects with Alzheimer's for up to 72 weeks”.
Thies said: "There is value in continuing to study rosiglitazone in Alzheimer's. We need to attack the disease through multiple mechanisms, and the only way we can learn with certainty about issues of safety and efficacy in Alzheimer's is through clinical trials."
"There are risks involved in clinical studies, and we do need to ensure that all risks are thoroughly described and explained to study participants and family members. That's why we have informed consent, and why the process is so important," he added.(23)

6) References
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2) Arnold, S.E., Hyman, B.T., Flory, J., Damasio, A.R., and Van Hoesen, G.W. 1991.The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex,  1:103-116. PUBMED 
3) Ballard, P.A., Tetrud, J.W., and Lanston, J.W.1985. Permanent human parkinsonism due to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): Seven cases. Neurology,  35:949-956. PUBMED 
4) Beal, M.F., Kowall, N.W., Ellison, D.W., et al.1986 Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature,  321:168-172. PUBMED 
5) Chase, T.N. Levodopa 1998.therapy: Consequences of nonphysiologic replacement of dopamine. Neurology,  50:S17-S25. 
6) Chatellier, G., and Lacomblez, L. Tacrine (tetrahydroaminoacridine; THA) and lecithin.1990.  senile dementia of the Alzheimer type: A multicentre trial. Groupe Francais d'Etude de la Tetrahydromaminoacridine. BMJ,  300:495-499. PUBMED 
7) Cohen, G., and Werner, P. 1994.Free radicals, oxidative stress and neurodegeneration. In, Neurodegenerative Diseases. (Calne, D.B., ed.) Saunders, Philadelphia,  pp. 139-161. 
8) Cotzias, G.C., Papavasiliou, P.S., and Gellene, R.1969. Modification of Parkinsonism: Chronic treatment with L-DOPA. New Engl. J. Med., 280:337-345. PUBMED
9) Cudkowicz, M.E., and Brown, R.H., Jr.1996. An update on superoxide dismutase 1 in familial amyotrophic lateral sclerosis. J. Neurol. Sci.,  139(suppl):10-15.
10)  Evans, D.A., Funkenstein, H.H., Albert, M.S., et al1989. Prevalence of Alzheimer's disease in a community population of older persons: Higher than previously reported. JAMA,  262:2551-2556.PUBMED 
11)  Ferrante, R.J., Kowall, N.W., Beal, M.F., et al1987.. Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington's disease. J. Neuropathol. Exp. Neurol.,  46:12-27. PUBMED 
12) Friedman, J.H., and Factor, S.A.2000 Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson's disease. Mov. Disord., 15:201-211. PUBMED 
13)  Frucht, S., Rogers, J.G., Greene, P.E., Gordon, M.F., and Fahn, S. 1999.Falling asleep   at the wheel: Motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology,  52:1908-1910. PUBMED 
14) Gibb, W.R1992.Neuropathology of Parkinson's disease and related syndromes. Neurol. Clin.,  10:361-376. PUBMED
15)  Hersch, S.M., Gutekunst, C.A., Rees, H.D., Heilman, C.J., and Levey, A.I.1994. Distribution of m1-m4 muscarinic receptor proteins in the rat striatum: Light and electron microscopic immunocytochemistry using subtype-specific antibodies. J. Neurosci.,  14:3351-3363. PUBMED 
16)  Hornykiewicz, 1973.. Dopamine in the basal ganglia: Its role and therapeutic indications (including the clinical use of L-DOPA). Br. Med. Bull.,  29:172-178. PUBMED
17) Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell, 1993, 72:971-983. PUBMED
18) Jenkins, B.G., Koroshetz, W.J., Beal, M.F., and Rosen, B.R.1993. Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy. Neurology,  43:2689-2695. PUBMED
19) Jenner, P. 1998.Oxidative mechanisms in nigral cell death in Parkinson's disease. Mov. Disord.,  13(suppl 1):24-34.
20)  Kurth, M.C., Adler, C.H., Hilaire, M.S., et al.1997. Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson's disease experiencing motor fluctuations: A multicenter, double-blind, randomized, placebo-controlled trial. Tolcapone Fluctuator Study Group I. Neurology, 148:81-87. PUBMED
21) Lacomblez, L., Bensimon, G., Leigh, P.N., Guillet, P., and Meininger, V.1996. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet,  347:1425-1431. PUBMED
22) Landwehrmeyer, G.B., McNeil, S.M., Dure, L.S., et al. 1995.Huntington's disease gene: Regional and cellular expression in brain of normal and affected individuals. Ann. Neurol.,  37:218-230. PUBMED
23) Lipton, S.A., and Rosenberg, P.A.1994. Excitatory amino acids as a final common pathway for neurologic disorders. New Engl. J. Med., 330:613-622. PUBMED
24) Mouradian, M.M., Heuser, I.J., Baronti, F., and Chase, T.N.1990. Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease. Ann. Neurol.,  27:18-23. PUBMED
25) Olanow, C.W.1993. MAO-B inhibitors in Parkinson's disease. Adv. Neurol., 60:666-671. PUBMED
26)  Olney, J.W.1969. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science,  164:719-721. PUBMED
27)  Parkinson Study Group. 1993.Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. New Engl. J. Med.,  328:176-183. 

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