Magoosh GRE

Alzheimer’s Disease

| March 14, 2015

Introduction
Alzheimer’s disease is a progressive, degenerative, and irreversible disorder of the brain. It is named after the German Psychiatrist Dr. Alois Alzheimer, who first noticed the structural abnormalities of the brain of a deceased woman with a history of mental illness. (NIA, 2011) As per the 2009 world Alzheimer’s report, Alzheimer’s is the most common form of dementia affecting around 35.6 million people around the world. The figure is slated to increase further with projections indicating that roughly 65.7 million people would be affected by the condition by 2030 and 115.4 million people by 2050. (Wilmo & Prince, 2010). There are four types of dementia of which Alzheimer’s is the most common representing about 50 to 70% of all cases of dementias. (European Commission, 2011) The others being vascular dementia, Lewy body dementia, and frontotemporal dementia. Alzheimer’s is predominant among the elderly population with the risk factors doubling every five years after 65 years of age. Statistics from the world Alzheimer’s report also indicate much higher prevalence rates in the developed and high income countries of Europe and America compared to Asia and other regions of the world. In the US, for example, Alzheimer’s affects as many as 5.4 million people with staggering annual costs of $183 billion. In the UK, the latest statistics suggest that around 465,000 people are affected by Alzheimer’s and the annual cost of caring for Alzheimer’s and other dementias is estimated at £20 billion. (Alzheimer’s Society, 2011) Overall, roughly around 5% of the world population above 65 and 20% of the population aged above 85 are afflicted by Alzheimer’s. With the soaring incidence rates dementia is now being considered a disorder rather than an inevitable old age condition. A brief overview of the symptoms, causes and the treatment methods would provide more insight into Alzheimer’s disease.

Alzheimer’s disease
Alzheimer’s is an irreversible, neurodegenerative disorder of the cortex region of the brain that leads to slow loss of memory and a general cognitive decline that cripples the day to day activities of the affected person. The symptoms of the disease are not easily obvious during the early stages as the human brain is very adaptive. This explains why most patients diagnosed with the condition are already in advanced stages with almost 80% of the brain cells damaged in the affected regions. The first stage of the disease is characterized by progressive memory loss as the cortical regions of the brain that are associated with memory are destroyed. As the condition progresses, regions of the brain that are associated with other cognitive functions are also affected which totally cripples the individual. This makes the Alzheimer’s patient unable to function independently.

$1The above Fig (1) is a frontal cross section of the brain that clearly shows the difference in brain structure of the normal brain compared with that of an Alzheimer’s patient. It is obvious that the grooves of the brain (the sulci) are noticeably widened in the Alzheimer’s patient’s brain. Also visible is the significant reduction of gyri or the folds of the brain in the Alzheimer’s brain. Furthermore, the ventricles of the brain that contain the cerebrospinal fluid are also noticeably enlarged in the Alzheimer’s brain. [AHAF, 2011]Throughout the progress of the disease there is a gradual decline of the outer layer or the cerebral cortex with a corresponding decline in all memory and other cognitive functions. MRI based volumetric measurements of the cortex region clearly highlight the damage to the cingulate cortex region. The following Fig 2 the cingulate gyrus borders.$2

Fig 2. MRI scan indicating the Sulci, Gyri and the cingulate gyrus borders in AD patients showing regional atrophy(Jones et.al, 2006)
On an average a patient survives for up to 8 to 10 years with the condition while there are also cases of patients who have lived 20 years with Alzheimer’s. In the US Alzheimer’s is the sixth leading cause of death and the only disease in the top 10 that could not be prevented or slowed down. In fact, while most diseases have recorded a reduction in mortality rates Alzheimer’s disease has shown a significant increase of up to 66%. (Alzheimer’s Association, 2011)The following graph (See Fig 3) depicts the serious nature and the growing mortality rates for Alzheimer’s disease. $3

In the UK also similar trends are observed. As per the 2010 statistics, deaths due to dementia have increased by 11%. Alzheimer’s disease is currently the third major cause of deaths among women in the country. Among men in the UK, there is also a significant surge in deaths directly related to Alzheimer’s. With a 21% increase in mortality rates it currently ranks as the eighth leading cause of deaths. These data suggest the severity and the growing nature of the problem. (Guardian, 2011)

Symptoms of AD
AD has a wide spectrum of symptoms ranging from memory loss or amnesia to Dyspraxia or having difficulties doing complex tasks. In advanced stages of the disease the patient is even unable to dress himself and needs round the clock care. Usually memory loss is related to failure to recollect recent happenings while older memories are intact. However, as the condition progresses, the patient may even be unable to recognize his own family members. This condition is known as prosopagnosia. Most patients also experience depression and other psychotic symptoms. From a physician’s perspective, treating depression in an AD patient gives new problems as the drugs that are usually prescribed for depression interfere with the treatment given for AD. Particularly, the anticholinergic activity of the drugs used for depression directly contradict the mainstay therapy provided by cholinesterase inhibitors. [Lovestone, 1998, pg 11-15]

Diagnosis
As discussed earlier, Diagnosis of AD is not very easy. If the physician suspects AD in a patient he could subject him to the Abbreviated Mental Test Score (AMTS). This cognitive screening test is very simple and is rated on a 10 point scale. If the patient is not able to score 10 then there is enough reason to suspect an underlying cognitive decline. As a next step the physician can make the patient undergo the MMSE (Mini Mental State Examination). If the doctor suspects dementia in the patient, then as a further step, brain imaging studies can be conducted. These neuroimaging studies would help the radiologists to a large extent to distinguish between AD and other natural, age associated structural changes of the brain. . (Lovestone, 1998, pg 43) Today however, with the availability of Positron emission tomography (PET) tests in hospitals it becomes much easier to identify defects in any region of the brain to the minute scale. In fact, PET allows the physician to study the real time metabolic rate inside the patient’s brain.
Alzheimer ’s disease: Causes
Though researchers are yet to identify clearly as to what causes the onset of Alzheimer’s in some people they have already identified several biological, environmental and life style factors that are associated with Alzheimer’s. Scientists have identified several biological markers and specific genes that are over expressed in Alzheimer’s patients. Recently there has been a plethora of research devoted to unravelling the underlying genetic risk factors for developing Alzheimer’s and much progress has been achieved in this direction. Lifestyle factors including dietary habits, physical activity and pre-existing conditions of blood pressure, cholesterol levels, and diabetes are also considered to play a role in the onset of Alzheimer’s. A previous history of head injuries is considered as one of the high risk factors for developing Alzheimer’s. Furthermore, research has also identified the use of certain drugs including non steroidal anti inflammatory drugs (NSAID) as a potential risk factor for developing the disorder. (Alzheimer’s Research Foundation, 2011). This multi-factorial origin combined with the difficulties in early spotting of the symptoms makes Alzheimer’s a difficult to diagnose disorder. However autopsy of the brain provides a conclusive diagnosis of Alzheimer’s as it clearly reveals the Neurofibrillary tangles and Amyloid Plagues, the two distinctive structural abnormalities observed in all Alzheimer’s patients.
Neurofibrillary Tangles
The presence of neurofibrillary tangles is one of the distinctive features of Alzheimer’s disease. These tangles are nothing but twisted fibers inside the neuronal cells. Neuronal cells have what is called microtubules or microscopic channels that are useful for transporting nutrients within the cell. Biochemical studies have identified an unusually high concentration of Tau, a protein component which is part of the microtubule structure inside the neuron cells. In the case of Alzheimer’s patients, these abnormal concentrations of the Tau protein cause structural damage to the microtubules which in turn affects the nutrient transport mechanism inside the neurons, leading ultimately to the deterioration of the cells. The loss of neurons affects the cholinergic transmission which impairs the cognitive performance of the patient. The following diagram clearly illustrates the distinctive formation of the neurofibrillary tangles in the Alzheimer’s patient. The difference between the healthy neuron cells and those with tangles are very visible. (AHAF, 2011)

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Amyloid Plaques
Another distinctive brain anomaly revealed from an autopsy of Alzheimer’s brain is the presence of amyloid plaques. (See Fig 4) Amyloids are nothing but proteins that are produced by the body. In normal humans these proteins are easily disintegrated but Alzheimer’s patients are unable to breakdown the Amyloid protein fragments. This results in their accumulation between the neuron cells forming hardened protein structures known as the amyloid plaques. These plaques formed of Amyloid and beta amyloid are insoluble and affect the communication between the neurons. The beta amyloid is particularly found to be toxic and one of the important factors in the formation of the amyloid plaques. Research into the study of Amyloid plaques has vastly increased our understanding of the mechanism of these plaque formations. The Amyloid precursor protein (APP), is the fundamental protein constituent of the amyloid plaques. Studies have revealed that the particular segment where the APP is cleaved and the particular choice of the enzyme (alpha secretase, beta secretase or gama secretase) results in the release of either sAPPα or the toxic sAPPβ. The release of sAPPα has beneficial effects as it promotes neuronal growth while the release of sAPPβ has toxic effects for the brain cells. The released beta amyloids tend to aggregate with each other and these are called as oligomers. These oligomer molecules are found to attach themselves to the synaptic receptors (particularly the glutamate receptor mGluR5) of the surrounding neuronal cells thereby inhibiting their functional abilities. The following diagram shows the varied consequences of the APP cleavage due to the effect of different enzymes. $5

Alzheimer’s Disease (the Genetic Link)
The field of genetic research is fast improving and over the years we have uncovered several genes that may have a role in the onset of AD. Three genes in particular, have so far been identified as presenting a direct risk for developing early onset AD. These include amyloid precursor protein (APP) gene and the presenilin genes PSEN-1 and PSEN-2. (Singleton et.al, 2000) Genetic aberration in the 21st chromosome in the APP gene is associated with the production of amyloid protein in the brain which is implicated as one of the culprits in AD. Similarly aberration at the 14th chromosome of the PSEN1 gene and 1st chromosome of PSEN2 gene are associated with early onset AD. Typically, people with such genetic anomalies tend to develop AD in their early thirties. There is also one gene known as the apolipoprotein E (APOE) which has been implicated as a risk factor for the onset of AD in aged people. (above 60 or 65). This gene comes in three different forms namely APOE2, APOE3 and APOE4. Out of these APOE4 gene is found to carry a heightened risk for developing AD. People with a dual copy of APOE4, are therefore predisposed to develop AD much earlier than those with a double copy of APOE2. More and more studies are uncovering further genetic links for AD. (Alzheimer’s Society, 2008)
With one in every four American having the APOE4 type, it is the most commonly occurring form of E(ApoE).(AHAF, 2012) Recent studies have focussed on the potential activity of the E(ApoE) along with the polymorphism of the cholesterol 24-hydroxylase (CYP46) gene. The underlying theory is that in AD patients the cerebral cholesterol metabolism is affected by the gene polymorphism, the most common of which is the CYP TT genotype. (Wang et.al, 2004) found that individuals who carry both the CYP TT genotype as well as the APOE ɛ4-allele carry an heightened risk for developing late onset Alzheimer’s disease (LOAD). (Wang et.al, 2004). A more recent study by Garcia et.al(2009) which comprehensively reviewed research linking APOE4 and the CYP46 polymorphisms over the last 9 years has also attested to this role of APOE ɛ4-allele and CYP T allele as well as C allele in the onset of LOAD. (Garcia et.al , 2009)

The SORL1 gene
As the genetic testing for AD improves researchers are identifying evidence for new genes and the role they play in the onset of AD. A recent Dutch research found the link between a new gene called SORL1 and AD. The researchers who conducted the study found that the SORL1 gene had a direct relation to the Hippocampal volume in young and healthy adults. The researchers found that a protein produced by the SORL1 gene mediates the APP and controls the formation of Aβ plaques in the brain. They also found that several varieties of the gene also have the link for AD. In this research the authors studied 900 healthy young adults using gene analysis and performed brain imaging studies particularly of the hippocampus region. Hippocampal volume was found to be related to the presence of SORL1 gene. Furthermore all four varieties of the gene had similar effects. Finally, the researchers also found that snip, that is a single nucleotide polymorphism (SNP) or mutation of a single DNA base, rs668387, had a profoundly positive correlation with AD. The study authors concluded that there is enough evidence for a possible direct link between the hippocampal volume and the SORL1 gene. Furthermore the polymorphic form of the SORL1 gene was identified as a contributor to the onset of AD by its degenerative effect on the hippocampal volume. (Treichel, 2011)

Treating Alzheimer’s
There is no known cure of Alzheimer’s as yet. Current therapy is mostly focused on managing the symptoms in order to provide the patient with a better quality of life. Therapeutic intervention also focuses on controlling the side effects of the disorder such as hallucinations, depression, etc. Currently, one of the main line therapies for Alzheimer’s disease is drugs that improve the cholinergic transmission in the brain. These drugs are important as they considerably improve the cognitive functioning ability of the patient and delay the neuronal damage. A brief discussion of cholinergic transmission would help us better understand this.

Improving Cholinergic Transmission
There are two types of nervous systems in the body namely the central nervous system and the peripheral nervous system. The CNS includes the brain and the spinal column while the peripheral nervous system includes all other nerves in the body. Normally when the electrical signals or what are knows as action potential travel along the nerve cells and reach the axon terminal they trigger the release of a neurotransmitter called acetylcholine which passes through the synaptic junction between the nerve and the organ or gland. Acetylcholine then reacts with the organ receptor triggering a series of chemical reactions that in turn produce the biological response. (muscle stimulation, contraction , etc) For this process to be normal it is very vital that the neurotransmitter acetylcholine is synthesized at the axon terminals. Furthermore, in order to correctly control and time these sequence of events the human body also releases another enzyme called acetylcholinesterase (AChe). The main purpose of this enzyme is to breakdown the acetylcholine immediately after the signal transmission along the synaptic junction. This mechanism provides a balance and acts as an effective control system that supervises the cholinergic transmission. (Smith) The following illustration clearly shows the role of the neurotransmitter acetylcholine in controlling biological functions of the organs.$6In the case of Alzheimer patients though, there is drastic effect on cholinergic transmission due to a significant deficit in the levels of the neurotransmitter Acetylcholine. Acetylcholine is a neurotransmitter which is active both in the Central Nervous System (CNS) as well as the peripheral Nervous System(PNS). ACH is released by the presynaptic neurons into the synaptic cleft where it activates the presynaptic receptors or post synaptic receptors or disintegrates into choline by the activity of the enzyme acetylcholinesterase. Two main types of ACH receptors are known namely Muscarinic receptors and nicotinic receptors both of which are found in the presynaptic as well as postsynaptic cleft. The below figure shows illustrates the various functions of the ACH neurotransmitter and the typ$7e of receptors that it interacts with. (Guzman, 2012).

FIG 7: Various Muscarinic receptors FIG 8: Types of Nicotinic receptors (Guzman, 2012)

The muscarinic receptors such as M1, M4,M5 are associated with various functions such as memory, arousal, sleep cycle etc. M2 is associated with heart rate control Of the two nicotinic receptors N1(Nm) and N2 (Nn) the Nm receptors are found only at the neuromuscular junction while the Nn plays a vital role in cholinergic transmission in the autonomous as well as the CNS. (Guzman, 2012) So the focus is on improving the cholinergic transmission by increasing the brain acetylcholine levels in Alzheimer patients. To achieve this, therapy is targeted on inhibiting the action of the cholinesterase (which breaks down acetylcholine). These drugs are together called as cholinesterase inhibitors and are widely used in the treatment of Alzheimer disease. Well known drugs that fall under this category are Aricept (Donepzil), Cognex (tacrine), Exelon (rivastigmine), razadyne (galantamine), etc. (AHAF, 2011
Mechanism of action of Cholinesterase inhibitors
Accumulating research evidence has confirmed that the main mechanism of action for cholinesterase inhibitors is acetylcholinesterase inhibition. In other words, this class of drugs known as Cholinesterase inhibitors work by mediating cholinergic signaling through controlling the availability of neuronal acetylcholine . There is also growing evidence for a cholinergic anti-inflammatory pathway, and the potential role of acetylcholine in inflammation inhibition. Improved cholinergic transmission has been associated with central and peripheral anti-inflammatory effects associated with reduced cytokine secretions. This alternative pathway of AcetylCholinesterase inhibitors (AchEI) is due to their potential effect on the immune system. In particular, modulating effect on cytokine secretions from the peripheral blood mononuclear cells (PBMC) of AD patients has been reported in the nueroprotective effects of this group of drugs. For instance, a marked decrease in levels of oncostatin M, interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) has been observed in patients treated with AchEI. Down regulating the cytokine secretions is one of the pathways of action for AchEI group of drugs. (Reale et.al , 2005)

Donepzil
Donepzil is one of the earliest drugs and was approved for the treatment of Alzheimer’s disease by the FDA in 1996 and still continues to be a main drug in the treatment of mild , moderate and severe cases of Alzheimer patients. The side effects of this drug include diarrhea , weight loss, vomiting, loss of sleep, loss of appetite, etc. Studies have indicated that the use of Donepzil hydrochloride could actually prevent the development of AD in subjects who are diagnosed with mild cognitive impairment (MCI). One study conducted in Japan by Hashimoto et.al (2005) studied the neuroprotective effect of the drug by using the hippocampal atrophy as a marker. For the study the researchers compared two groups of Alzheimer patients. One group comprising of 54 patients were provided with Donepzil hydrochloride as the mainstay treatment while the other group consisted 93 AD patients who received no drug intervention. MRI scans of their brain were taken annually and the degree of hippocampal atrophy measured. The researchers carefully selected the subjects such that the baseline parameters including age, sex , education and apolipoprotein E (APOE) genotype are more or less similar between the two groups. Results based on the MRI volumetric analysis revealed significant difference between the two groups. The group that received Donepzil treatment had an average annual rate of hippocampal volume loss of (mean=3.82%, SD=2.84%) while the control group had a markedly higher annual hippocampal volume loss of (mean=5.04%, SD=2.54%). Even after adjusting for the differences in baseline variables, there was still a marked difference between the two groups clearly suggesting that the cholinesterase inhibitor Donepzil has a neuroprotective effect and helps to slow down the severity of AD. (Hashimoto et.al , 2005)
Rivastigmine
Rivastigmine is another class of cholinesterase inhibitors that works by inhibiting the breakdown of acetylcholine and another chemical found in the brain called butyrylcholine. The drug has similar side effects of stomach upset, nausea, weight loss, dizziness, etc. It was approved by the FDA in 2000 and has been used extensively in the treatment of AD as well as Parkinson’s disease. In 2007 a new transdermal patch version of the drug was made available. This was mainly to avoid the negative effects that the drug has on the stomach. Recent studies have shown that treatment with Rivastigmine considerably improves the cognitive functioning of patients as noted by the score on the Alzheimer’s disease Assessment Scale (ADAS-cog). In one study by Weintraub et.al (2011), the researchers compared the effects of Rivastigmine on both AD and Parkinson’s patients. To evaluate the effects of the drug the researchers compared the ADAS scores of the AD, PDD (Parkinson disease dementia) as well as the control group that received no treatment. The researchers noticed that both the AD and the PDD group showed noticeable improvements in their cognitive scores compared to the placebo control group (P < .0001). In particular, there was significant increase in scores relating to memory and language in both the experimental groups compared to the control group suggesting a strong positive treatment effect for Rivastigmine. (Weintraub et.al 2011)

Grossberg et.al (2011) is another recent study involving Rivastigmine and its efficacy in the treatment of AD. This was a randomized study with a total of 892 patients who were suspected to have AD. The patients were given either an oral dosage of Rivastigmine 6mg tablets twice a day or Rivastigmine transdermal patches (9.5 mg/24 hours [10 cm2]) to be worn on the skin or a placebo drug. The study subjects received treatment over a 24 week period at the end of which their respective cognitive skills were evaluated by comparing their scores on the Alzheimer’s Disease Cooperative Study—Activities of Daily Living (ADCS-ADL). The respective scores compared to the placebo were (Rivastigmine patch, P = .013; capsules, P = .039). In particular for high level ADL functions Rivastigmine patches scored significantly better than placebo (P = .056). The results from this study affirm that Rivastigmine has strong cholinergic properties and significantly improves the cognitive functioning among AD patients. (Grossberg et.al, 2011)

Cognex (Tacrine)
Cognex (Tacrine) , the other FDA approved drug that was actively used in AD treatment is currently not actively promoted as the drug gave rise to severe side effects. Beside the usual symptoms of dizziness, vomiting and muscle cramps, the drug also carried a high risk for liver damage. This pronounced risk for liver toxicity is the main reason for declining use of Tacrine in the treatment of AD. However, Tacrine has been very powerful in terms of its cholinesterase inhibitory activity.
Conjunctive Therapy (combining anti inflammatory drugs and Cholinesterase Inhibitors)
Research is underway in developing new Tacrine derived compounds that are both effective and less toxic to the body. One recent research focused on the possible use of a tacrine based conjunctive treatment approached that would have a multi modal treatment focus. In particular, this research, based on studying the effect of Tacrine mefenamic acid hybrids focused on utilizing the combined effect of both the ChE inhibitors potential of Tacrine as well as the anti inflammatory properties of mefenamic acid. The following structural diagram shows Tacrine and mefenamic acid.

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This combination is proposed to provide a synergistic effect in slowing down the symptoms of AD. For instance it is known that in the presence of peroxidases, mefenamic acid acts as an inhibitor of AChE. Furthermore, mefenamic acid also expresses properties of countering free radicals and in the process slowing down the formation of Aβamyloids which is one of the predominant features of AD. The researchers developed several biofunctional inhibitors of AChE using tacrine and mefenamic acid. Biochemical assays were then performed to measure their therapeutic potential and their IC50 values obtained. An ROS inhibition assay was also used to identify its induced effect on the inactivation of AChE. The IC50 values showed a significant decreased compared to similar values with ROS. All the tacrine mefenamic acid hybrids showed similar ROS IC50 values (under one order of magnitude) clearly suggesting a powerful synergistic effect for Tacrine – mefenamic acid hybrids making them excellent candidates of choice for future drug development. However, more studies are required to assess the secondary effects of the hybrid molecules. These new AChE inhibitors that also control the Aβ peptides are expected to drastically improve the treatment outcome measures for AD patients in the near future. (Bronstein et.al , 2011)

Another Korean study by Joo et.al (2006) also proved the positive effects of Mefenamic acid in the treatment of AD. This research reported the results of both in vitro and in vivo studies. Particularly the study reported that mefenamic acid had an attenuating effect on the neuro toxic effects of amyloid beta peptides and also controls the mutations of APP. Also, the researchers reported positive improvements in memory and cognition in rats that were affected by Aβamyloid infused AD. (Joo et.al , 2006). Thus the therapeutic role of mefenamic acid in the treatment of AD is clearly evident.
Mechanism of action for Memantine (NMDA drug)
Namenda is one of the neuroprotective drugs available for the treatment of AD. The mechanism of action of Namenda is different from the other cholinesterase inhibitors discussed so far. NMDA receptor activity controls the excitability of the neuronal circuits. Namenda works differently by controlling glutamate, a chemical messenger released in excess by cells that are damaged by AD. This it does by targeting the glutamate receptors and blocking them. This is achieved by mediating the glutamatergic excitotoxicity in the neuron cells by blocking the current flow on the N-methyl-d-aspartate (NMDA) receptors channels. This excess glutamate attaches itself to the N-methyl-D-aspartate-sensitive glutamate receptors (NMDA) on the cell surface. This affects the ion exchange balance as it results in increased ca+2 influx into the cell. Excessive Ca2+ influx has a deteriorating effect on the cell by increasing free radical formation. Namenda only selectively impacts the NMDAR activity. In particular, Namenda only targets the extrasynaptic receptors while leaving the synaptic NMDAR activity unaffected. This is ideal as only the extra-synaptic receptors are known to cause neuronal damage. This preferential activity of Namenda at clinical concentrations makes it an excellent choice of treatment for AD as it does not interfere with the physiological synaptic activity. (Xia et.al, 2010)

Increased glutamate tends to create a chain reaction of neuronal damage. Being an NMDA antagonist, Namenda works by selectively blocking the abnormal transmission and the related exitotoxic effects. In this way Namenda reverses NMDA triggered cognitive deficiency. Namenda is well tolerated by patients with minimal side effects such as drowsiness, headache and high BP. However, care must be taken when using Namenda with other medications as it undergoes nonhepatic metabolism. Since Namenda is excreted by the kidneys any medication such as diuretics that make the urine alkaline may affect the elimination of Namenda increasing the risk of adverse reactions. [Forest Laboratories, 2003]

A study by Reisberg et.al (2003) attested to the positive effects of Namenda in the treatment of patients with AD. For this study, the researchers randomly grouped patients with moderate to severe AD to receive either 20 mg Namenda or a placebo drug. This program continued for a 28 week period. The ‘Clinician’s Interview-Based Impression of Change Plus Caregiver Input’ (CIBIC-Plus) as well as the ‘Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia’ (ADCS-ADLsev) were the two guiding variables used by the researchers to study the efficacy of Namenda. In total 181 patients completed the study and the results from the study indicated that subjects who received Namenda fared much better than the control group in both the CIBIC-Plus (P=0.06) as well as the ADCS-ADLsev (P=0.02) scales. The study also reported that Namenda was well tolerated in all patients with no adverse effects. ( Reisberg et.al , 2003)

Gene Therapy
Though still in its infancy the prospects of gene therapy look bright and could potentially be the saving grace for people with AD. In AD patients there is an observed loss of Nerve Growth Factor(NGF) which is thought to lead to shrinkage in cholinergic neurons. (Lim et.al, 2010) Already researchers have commenced clinical trials of genetic therapy and the outcome seems very encouraging. One such clinical trial completed the phase 1 recently with positive results. This study was sponsored by Alzheimer’s Disease Cooperative Study (ADCS) together with the NIA and NIH. The researchers of this study used CERE-110 gene therapy in patients with moderate AD. This gene is known to trigger the (NGF) in the neurons. This is achieved by delivering the NGF gene into the neuronal cells and by the natural cellular machinery the gene makes possible the replication of NGF molecule.(Brazell, 2011) Since NGF is the naturally occurring growth factor that nourishes the neuronal growth the researchers opine that increasing the availability of ‘Nerve Growth Factor’ would help the neurons to repair themselves and produce more of acetylcholine which is essential for cholinergic transmission. Already phase one of the trials are over with successful outcomes. The ten subjects who underwent the phase 1 trials all showed marked improvement in cognitive skills and the positron emission tomography tests of these subjects showed increased brain metabolism when compared to other AD patients who did not receive the therapy. In the follow up studies over a 4 year period the researchers did not see the subjects exhibiting any adverse reaction to the therapy. (Science Daily, 2010)

Conclusion
Alzheimer’s disease is a serious old age health issue across the world. The disease causes considerable physical and emotional stress on the patient as well as the caregivers. So far diagnosis has been complicated and most patients are diagnosed only when their condition is already moderate to severe. Neurofibrillary tangles and Amyloid plaques, the two definitive diagnostic features of AD, are only revealed in an autopsy. Hence there is still the need for more effective diagnostic methods that could help us with the early identification of the disorder. Particularly, the development of biological markers is very crucial. For instance, cholinergic markers such as choline acetyl transferase (CAT), acetylcholinesterase (AChE) and amyloid markers would help us with early diagnosis of the condition. Advancements such as PET that bring real time neuro imaging technology in to the diagnostic process are expected to aid the early diagnosis. Having no single cause and multi-factorial risk factors including genetic, environmental and lifestyle factors only complicate the treatment of AD. Up to now, cholinesterase inhibitors and anti inflammatory drugs have constituted the primary therapy for AD. The advancements in genetic analysis and the new breakthroughs in pharmaceutical therapy including the development of conjunctive multi modal therapies offer us new hope for better treatment outcome in the future. It is also important to understand the side effects that prolonged drug therapy could have on the patient. Besides providing pharmacological treatment to the patient, it is also necessary to understand the needs and the coping skills of the family members who take care of the AD patient. An integrated approach is essential for delivering the highest quality of care.

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