Alzheimers Disease Current Research And Treatment Biology Essay

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In 2006, the worldwide prevalence of Alzheimer's disease was 26.6 million. By 2050, prevalence will quadruple to 106.2 million with 1 in 85 persons worldwide will be living with the disease. As the world's population ages, we will face a looming epidemic of Alzheimer's disease. Since there is no treatment can cure Alzheimer's disease so far, and the predicted median survival times for females diagnosed at ages 65, 75 and 85 were only 9.1, 7.2 and 4.3 years respectively, the prevention and the improvement on the current treatment of Alzheimer's disease are very important. [1] 

A research group from Sweden's Karolinska Institute has attempted to estimate the worldwide cost of Alzheimer's disease and its amounts to US$315 billion per year including direct costs and informal care, of which US$227 billion (72% of the worldwide total) is contributed by high income countries and US$88 billion (28% of the total) by low and middle income countries. It shows that Alzheimer's disease cause a great financial loss around the world.

In addition, caregivers of the Alzheimer's disease patients have high probability of suffering financial stress and psychological disorders. Caregivers of patients with Alzheimer's disease spent an average of 1.6 hours daily in assisting with core personal activities of daily living including washing, dressing, grooming etc. If we include the time spent in assisting instrumental activities of daily living such as cooking, shopping, laundry etc, the figure will be increased to 3.7 hours. When general supervision was also taken into account the average care input was 7.4 hours per day. This long caring time will cause significant stress on the caregivers.

Many studies have also reported very high levels of psychological morbidity among caregivers of patients with Alzheimer's disease, which are 40% to 75% in as observed in EUROCARE project. A recent systematic review identified 10 studies which assessed the prevalence of major depressive disorder among caregivers of patients with Alzheimer's disease using structured clinical interviews, and the prevalence varied between 15 and 32%. In six of these studies the prevalence of major depression was compared with that in a control sample, with the prevalence in caregivers being 2.8 to 38.7 times higher. Therefore, Alzheimer's disease does not only cause disability of the patient, it can also lead to different kinds of psychological disorders in caregivers. And a high proportion of caregivers had to cut back on their paid work to care, e.g. 30.4% in rural China, and 19.2% in Cuba. It also causes a great financial stress in the patient's family. [2] 

Pathogenesis of Alzheimer's disease:

Alzheimer's disease caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaque.

Also, every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In Alzheimer's disease, tau undergoes chemical changes, and becomes hyperphosphorylated. The phosphorylated tau then begins to pair with other threads, creating neurofibrillary tangles, with resultant disruption of the neuron's transport system.

Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in mitochondria of Alzheimer's-affected brains and also inhibits the functioning of several enzymes and the utilization of glucose by neurons. However, as to how disturbances of production and aggregation of beta amyloid peptide give rise to the pathology of Alzheimer's disease is still unclear. Alzheimer's disease remains to be incurable. [3] 

Therapeutic Intervention of Alzheimer's disease

Traditional drug therapy

There are two major groups of drug that used to treat the cognitive manifestations of Alzheimer's disease. One group is acetylcholinesterase inhibitors such as Donepezil, Galantamine and Rivastigmine, another group is NMDA receptor antagonist such as Memantine.

Donepezil is a centrally acting as a reversible acetylcholinesterase inhibitor. It reduces the increased activity of cholinergic neurons, which is a well-known feature of Alzheimer's disease.4 Acetylcholinesterase inhibitors are commonly employed to reduce the rate at which acetylcholine is broken down, thereby increasing the concentration of acetylcholine in the brain and combating the loss of acetylcholine caused by the death of cholinergic neurons. Donepezil has an oral bioavailability of 100% and easily crosses the blood-brain barrier. Because it has a half life of about 70 hours, it can be taken once a day. Initial dose is 5 mg per day, which can be increased to 10 mg per day after an adjustment period of at least 4 weeks. It has more side-effects when compared with other groups of drug prescribed for Alzheimer's disease.

Donepezil has advantages over tacrine: (1) Donepezil is more selective than tacrine for neuronal acetylcholinesterase and does not appear to affect butyrocholinesterase; (2) it can be administered once daily, due to its longer half-life; and (3) it has been found to improve sleep apnea in Alzheimer's patients. On the other hand, the disadvantages of Donepezil compared to tacrine include: (1) it may cause GI symptoms such as nausea, vomiting, and loose stools, which occur in 5% to 10% of patients and are usually mild and transient; (2) it may cause muscle cramps and sleeps disturbances; (3) it is expensive, with annual cost to the patient or third-party payer typically ranging from $1,500 to $2,000; and (4) it may not improve the cognitive function in patients with severe Alzheimer's disease symptoms.

Memantine is a low affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, which forms the basis of neuronal excitotoxicity. Therefore memantine can be used to prevent neuronal cell death. The low affinity and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel preserve the physiological function of the receptor. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. However, there is no evidence for supporting the use of memantine to protect against NMDA receptor-mediated excitotoxicity.

Memantine is also a non-competitive antagonist at the serotonergic (5-HT3 receptor) and nicotinic acetylcholine receptor (nAChRs), but the clinical significance of the serotonergic activity of Memantine in the treatment of Alzheimer's disease is unknown.

While the effect of memantine is significantly stronger in severe patients of Alzheimer's disease than the mild or moderate patients, it possesses several therapeutic advantages: (1) Fast onset of action; (2) a long duration of effect lasting as long as seven to 30 days; (3) fewer side effects as its affinity to the NMDA receptor is low at therapeutic dose, and (4) it is increasingly effective against escalating levels of glutamate, such as those observed during a stroke. [4] On the other hand, the disadvantages of memantine include : (1) it produces schizophrenia-like effects; [5] and (2) it is not effective in mild to moderate patients of Alzheimer's disease

Recently, some researchers have shown that Latrepirdine, originally marketed as an antihistamine drug, can be used to combat with Alzheimer's disease. Latrepirdine appears to operate through multiple mechanisms of action, both blocking the action of neurotoxic beta-amyloid proteins and inhibiting L-type calcium channels, modulating the action of AMPA and NMDA glutamate receptors, and producing a neuroprotective effect by blocking a target that involves the opening of mitochondrial transition pores, which are believed to play a role in the cell death associated with neurodegenerative diseases. Recent studies showed that at higher concentrations (100 nM) of Latrepirdine, it appeared to protect mitochondria from the toxic effects of Amyloidβ42. However, there is yet no link between mitochondrial membrane potential and synaptic function or cognition. [6] 

The outcome of a phase III clinical trial released in March 2010 is disappointing . It was shown that the investigational Alzheimer's disease drug, Latrepirdine, failed in the pivotal connection trial of patients with mild-to-moderate disease. In the study, neither the placebo nor the Latrepirdine groups showed any significant change from baseline in the ADCS-ADL (Alzheimer's disease Cooperative Study-Activities of Daily Living). [7] 

Potential new therapies of Alzheimer's disease

As the conventional drug therapies for Alzheimer's disease have a lot of side-effects and cannot cure but only delay the progression of the disease, scientists is eager to search for new drugs or alternative therapies to prevent or cure Alzheimer's disease

Nanoparticle radiation [8] 

Chemists in China and Spain have identified a potential new therapy to destroy the insoluble beta-amyloid fibrils and plaque that contribute to the onset of Alzheimer's disease. They attached gold nanoparticles to a group of beta-amyloid fibrils, incubated the resulting mixture for several days, the fibrils subsequently dissolved and remained the same so far at least one week after being irradiated. The results indicated that the nanoparticle radiation treatment was not only effective in breaking up the fibrils, but also resulting in a lower tendency of proteins to aggregate. The energy level of the radiation used was six times lower than that of cell phones and it unlikely produces any harmful effect on healthy cells. Therefore, it may represent a new way to slow down the progression of Alzheimer's disease without any side-effects, which is superior to currently used drugs.

CERE-110  [9] 

CERE-110 is an adeno-associated virus-based gene delivery vector that encodes for human nerve growth factor for stereotactic surgical delivery to the human nucleus basalis of Meynert. Protecting and restoring the basal forebrain cholinergic neurons (BFCNs) of the nucleus basalis of Meynert (NBM) is a logical approach to treat mild to moderate Alzheimer's disease because Alzheimer's disease involves the death of cholinergic neurons in BFCNs and NBM. Gene transfer may be the most effective and practical delivery method available, in that it can provide controlled and sustained delivery of a therapeutic protein such as nerve growth factor to a targeted brain region following a single surgical procedure, without the complications of indwelling hardware.

CERE-110-mediated nerve growth factor delivery might show cognitive benefit similar to the acetylcholinesterase inhibitors, since nerve growth factor is predicted to effectively increase availability of acetylcholine in the cerebral cortex. However, CERE-110 provides significant additional cognitive benefit by preventing the death of BFCNs, increasing the vitality of remaining BFCNs, and generating more acetylcholine in the cortex than do acetylcholinesterase inhibitors. This is of particular therapeutic significance since the systemically administered acetylcholinesterase inhibitors have significant dose-limiting toxicity associated with peripheral cholinesterase inhibition. 

AAV2 vector was chosen because it preferentially transfects neurons, delivers the transgene predominantly as non-integrated DNA (thereby reducing the possibility of insertional mutagenesis), and results in long-lasting gene expression following a single administration to the brain parenchyma.

Outcome from the phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer's disease suggested that the gene therapy had the improvement in the rate of cognitive decline and no long-term adverse effects of NGF were observed.

IgG-single chain Fv fusion protein [10] 

Monoclonal antibodies directed against the beta amyloid peptide of Alzheimer's disease are potential new therapies for Alzheimer's disease, since these antibodies disaggregate brain amyloid plaque. However, the monoclonal antibodies (MAb) are not transported across the blood-brain barrier. To enable blood-brain barrier transport, a single chain Fv (ScFv) antibody against the beta-amyloid peptide of Alzheimer's disease was re-engineered as a fusion protein with the monoclonal antibodies against the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry the ScFv therapeutic antibody across the blood brain barrier.  

One experiment demonstrated the ability of HIRMAb-ScFv fusion protein to bind to the beta-amyloid in animal cells. Chinese hamster ovary (CHO) cells were stably transfected with a tandem vector encoding the heavy and light chains of the HIRMAb-ScFv fusion protein. A high secreting line was isolated following methotrexate amplification and dilutional cloning. The HIRMAb-ScFv fusion protein in conditioned serum-free medium was purified by protein A affinity chromatography. The fusion protein was stable as a liquid formulation, and retained high-affinity binding of both the HIR and the beta-amyloid peptide.

Another experiment showed the ability of HIRMAb-ScFv fusion protein to move across the blood brain barrier. The HIRMAb-ScFv fusion protein was radio-labeled with the (125)I-Bolton-Hunter reagent, followed by measurement of the pharmacokinetics of plasma clearance and brain uptake in the adult Rhesus monkey. The HIRMAb-ScFv fusion protein was rapidly cleared from plasma and was transported across the primate BBB in vivo.

Therefore, the HIRMAb-ScFv fusion protein is a new class of antibody-based therapeutic for Alzheimer's disease that has been specifically engineered to cross the human Blood Brain Barrier.

Ginkgo biloba [11] 

A standardized extract of Ginkgo biloba leaf EGb 761, a phytomedicine serived from traditional Chinese medicine, has been reported to protect the brain against hypoxic damage and to inhibit the reactive oxygen species (ROS) formation in neurons. The mechanisms underlying the protective effects of EGb761 remain unclear. It is possible that it may be associated with increasing activation of bcl-2, maintaining the stability of mitochondrial membrane potential, and decreasing the activation of caspase-3 through the mitochondria-dependent pathway in cells. All these actions promote cell survival.

EGb761 may inhibit circulating beta-amyloid entering the brain via a leaky blood brain barrier under hypoxia and hypoglycemic conditions, with resultant increase transport of beta-amyloid from brain to bloodstream. EGb 761 has been shown to block the formation of free radical. [12] 

To conclude, EGb761 could have a capability to readjust the transport equilibrium for beta-amyloid by promoting its efflux from brain into bloodstream and inhibiting its influx from bloodstream into brain, thereby enhancing the clearing beta-amyloid from brain.

Cannabinoids [13] 

Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. These findings suggest the localization, expression, and the function of cannabinoid receptors in Alzheimer's disease and the possible protective action of cannabinoids againstn beta-amyloid-induced neurotoxicity.

Clinical studies showed that CB1 receptor protein expression were markedly decreased in Alzheimer's disease brains. Additionally, in Alzheimer's disease's brains, protein nitration was increased, and CB1 proteins showed enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats could prevent beta-amyloid-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) blocked beta-amyloid-induced activation of cultured microglial cells, as assessed by mitochondrial respiratory activity, cell morphology, and tumor necrosis factor-beta release. And these effects were independent of the antioxidant action of cannabinoid compounds and were also exerted by a CB2-selective agonist. Moreover, cannabinoids abrogated microglia-mediated neurotoxicity after the addition of beta-amyloid to rat cortical cocultures.

The results therefore indicate that cannabinoid receptors are crucially involved in the pathogenesis of Alzheimer's disease and that cannabinoids can prevent the neurodegenerative process in Alzheimer's  disease.


Tarenflurbil is the single enantiomer of the racemate NSAID flurbiprofen.

Flurbiprofen(S-enantiomer) and Tarenflurbil(R-enantiomer) selectively lower beta- amyloid42 levels in broken cell γ-secretase assays, indicating that these compounds directly target the γ-secretase complex that generates beta-amyloid from amyloid protein precursor. Since R-flurbiprofen, which has reduced side-effects arising from the inhibition of cyclooxygenase (COX), reduces beta-amyloid42 level by targeting γ-secretase, it is an excellent candidate for clinical testing as a beta-amyloid42 lowering agent. As beta amyloid42 is the more fibrillogenic form and is thus associated with disease states, selective breaking down the beta amyloid42 is important in Alzheimer's disease's treatment. The mild inhibition of COX also enables the administration of the drug at higher doses.

Additional studies will be needed to determine the precise mechanism underlying the interaction between flurbiprofen and γ-secretase. Although no studies are available regarding the long-term effect of flurbiprofen and its enantiomers on APP transgenic mice, a nitrous oxide-releasing flurbiprofen derivative, NCX-2216, has been reported to be highly effective in reducing beta-amyloid accumulation in long-term mouse model of Alzheimer's disease. NCX-2216 is converted to flurbiprofen in vivo and interact with -secretase.

Tarenflurbil can inhibit NF-κB. The inhibition of NF-κB has been postulated to reduce the inflammatory response in Alzheimer's disease. As the inflammatory mechanisms in the brain may contribute to the neurodegenerative process in Alzheimer's disease, the inhibition of NF-κB may therefore slow down the progression of Alzheimer's disease. However, the beta-amyloid42 lowering effect of Tarenflurbil and the inhibition effect on NF-κB appear to be independent of each other. Taken together, Tarenflurbil is a compound that can be used to test the hypothesis that beta-amyloid42 levels can be safely lowered in humans with minimal effects on COX activity or physiological functions of γ-secretase. Clinical testing of Tarenflurbil on beta-amyloid42 lowering effect will be necessary to determine if it has a therapeutic potential in Alzheimer's disease.  [14] 15


PBT2 is a small, orally bioavailable molecule which has been designed to inhibit catalytic redox activity of beta-amyloid related to its abnormal binding to copper. As a consequence of its metal ionophore properties, PBT2 is believed to act secondarily by promoting normal copper and zinc homeostasis in the brain, redistributing these crucial metals to their correct anatomical compartments, and preventing further pathological interactions with beta-amyloid.

Beta-amyloid is a high-affinity metal binding protein which adopts a toxic gain of function in the presence of copper and zinc. PBT2 acts at three levels of the "amyloid cascade": (1) it inhibits the redox-dependent formation of toxic soluble oligomers, (2) prevents deposition of beta-amyloid as amyloid plaques, which are believed to be the toxic chemical entity leading to brain damage in Alzheimer's disease, and (3) promotes clearance by mobilizing and "neutralizing" beta-amyloid from existing deposits. [16] 

In addition, a study showed that PBT2 in the rodent brain blocked synaptotoxicity caused by soluble beta-amyloid oligomers and restored LTP (long-term potentiation) -- the neuronal electrical activity that underlies memory formation. Therefore, PBT2 may not only facilitate the clearance of beta-amyloid from the brain or prevent its production, but also, more importantly, improve cognition.

Based on a growing body of encouraging experimental evidence on PBT2, a Phase II, double-blind, placebo-controlled trial of PBT2 on Alzheimer's patients is under way. [17] 

Etanercept [18] 

Etanercept is a fusion protein comprising domains from a Tumor necrosis factor-alpha (TNF) receptor fused to the Fc portion of IgG1 and binds to tumor necrosis factor-alpha, and decreases its role in inflammation of nervous tissue.

Tumor necrosis factor-alpha (TNF) is one of cytokines that generally act to promote acute-phase reactions but can drive degenerative changes when chronically elevated. Of particular relevance to intersections between neuroinflammation and neurodegeneration is the ability of TNF to increase expression of interleukin-1 (IL-1), which in turn increases production of the precursors necessary for formation of amyloid plaques, neurofibrillary tangles, and Lewy bodies. These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation, and synaptic dysfunction e.g.Alzheimer's disease.

Toward such manipulation in Alzheimer's disease, a six-month study was conducted with 15 probable-Alzheimer patients who were treated weekly with perispinal injection of Etanercept, that is now widely used for treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for Alzheimer patients.

The rapidity with which cognitive and behavioral functions are recovered by the patient may due to etanercept capture of excess glia-derived TNF, which results in reversal of synaptic dysregulation. And Fc portion of IgG1 is fused to the TNF protein due to the anti-inflammatory effects of certain Fc receptor ligands. So, etanercept treatment may have a generalized effect on the immune system due to Fc receptor ligation. Calculations, based on stoichiometry of binding and clearance, suggest the possibility that the effects of anti-beta amyloid antibodies result from such an antigen-independent mechanism. Exploration of the functional consequences of the Fc fusion domain in etanercept might reveal this agent to be a combination anti-TNF/"passive immunization" therapy.

To conclude, there are a lot of possible therapies are undergoing research, most of them do not have the side-effects of the traditional drug therapy and shows a variety of possible mechanism to treat Alzheimer's disease, e.g. dissolving the beta-amyloid, prevention the formation of beta-amyloid or adjust the equilibrium of beta-amyloid in the brain to remove the beta-amyloid in the brain. Most of them are effective than the traditional drug therapy as they potentially treating the underlying disease pathology, which is the reduction of beta-amyloid rather than slow cognitive decline which do not alter underlying disease progress.

Prevention of Alzheimer's disease

Alzheimer's disease is an incurable disease, the patients and his families, the societies are burdened by this disease significantly. The economic lost due to Alzheimer's disease is greater than US$300 billion every year around the world. Therefore the prevention of Alzheimer's disease is very important.

At present, there is no definitive evidence to support that any particular measure is effective in preventing Alzheimer's disease. Global studies of measures to prevent or delay the onset of Alzheimer's disease have often produced inconsistent results. However, epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing Alzheimer's disease. 

Coffee and tea drinking [19] 

Caffeine stimulates central nervous system on a short term. However, the long-term impact of caffeine on cognition remains unclear. A research showed that the association between coffee and/or tea consumption at midlife and Alzheimer's disease risk in late-life. Participants of the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were randomly selected from the survivors of a population-based cohorts previously surveyed within the North Karelia Project and the FINMONICA study in 1972, 1977, 1982 or 1987 (midlife visit). After an average follow-up of 21 years, 1409 individuals (71%) aged 65 to 79 completed the re-examination in 1998. A total of 48 cases were identified as Alzheimer's disease. Coffee drinkers at midlife had lower risk of dementia and Alzheimer's disease later in life compared with those drinking no or only little coffee adjusted for demographic, lifestyle and vascular factors, apolipoprotein E epsilon4 allele and depressive symptoms. The lowest risk (65% decreased) was found in people who drank 3-5 cups per day. Tea drinking was relatively uncommon and was not associated with dementia/Alzheimer's disease. Coffee drinking at midlife is associated with a decreased risk of dementia/ Alzheimer's disease later in life. This finding shows the possibilities for prevention of dementia/ Alzheimer's disease.