What’s wrong with the existing treatment for Alzheimer’s diseaseAlzheimer’s disease (AD) is a common type of age-related dementia, associated with brain infarction due to the loss of brain cells, which continues to deteriorate over time. The two major pathological features of AD are ?-amyloid plaques, which are fragments of amyloid precursor protein (APP) (Rang et al., 2007), and neurofibrillary tangles, which consist primarily of hyperphosphorylated forms of a microtubule-associated protein, Tau (Cuello, 2008). Mutation of the APP genes increase the formation of A?40 and A?42, occurring aggregation of A? which is easier undergo in the Apolipoprotein E4 (apoE4) gene presented condition. Processing of APP results in the composition of amyloid plaques and neurofibrillary tangles, which lead to neuronal death (Rang et al., 2007). With an increasing number of dead brain cells, patients may suffer from memory lapses, aphasia, and dysphagia at the early stage of Alzheimer’s, middle-stage, and later stage, respectively (NHS, 2016). There is a gradual decline in bodily functions when these symptoms worsen, ultimately leading to death. Approximately 850,000 people in the UK suffered from AD in 2015, and the number of patients in the UK is forecasted to increase to more than one million by 2025 (NHS, 2016). Accordingly, we can observe a lack of existing drugs for treating and improving functional measures related to quality of life where Alzheimer’s is concerned. This essay will discuss the mechanisms and problems of two main types of medications in the treatment of AD: acetylcholinesterase inhibitors (cholinesterase inhibitors) and NMDA (N-methyl-D-aspartate) receptor antagonists. Finally, expectations and information about drug development will be presented.In AD treatment, the most widely used cholinomimetic agent are acetylcholinesterase inhibitors (AChE inhibitors). AChE inhibitors are defined as enzymes that break down the neurotransmitter acetylcholine (ACh) (Martin, 2015). These inhibitors can be classified into two main classes: reversible and irreversible enzyme inhibitors, which extend into four sub-types under reversible inhibitors: competitive, uncompetitive, non-competitive, and mixed inhibitors. Both of these two types of drugs support AD sufferers’ cholinergic system by obstructing the degradation of ACh; however, reversible AChE inhibitors play a more important role in the pharmacological manipulation of enzyme activity. Reversible inhibitors bind non-covalently to enzymes; non-covalent interactions between inhibitors and enzymes include hydrogen bonds, hydrophobic interactions, and ionic bonds. Reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme, and it can easily be removed by dilution, i.e., the enzyme can be activated again to retain a balance between blocking and stimulation. Additionally, drug toxic level is lower compared with irreversible inhibitors. In AD, AChE inhibitors inactivate AChE enzymes by occupying the reacting position.The inhibitor adds the anionic site of the enzyme, forming an ionic bond with glutamate-(334). Since the AChE inhibitor carries a positive charge after binding with Glu-334, an amino acid attaches to a carboxylic acid group with a negative charge. The initial purpose of donating a proton is to bring AChE into the active site. Nonetheless, the enzyme function will not perform when it instead receives the AChE inhibitor. However, the ionic interaction is not stable, which means the process is reversible and temporary. Donepezil (Aricept) is an example of a short-acting reversible AChE inhibitor, which is permitted for mild to moderate AD in 1996 (Shaikh et al., 2014). This drug helps in retarding the deposition of amyloid plaque (Colovic et al., 2013) by binding to the peripheral anionic, because of the unique orientation facilitates site (Shaikh et al., 2014).Another reversible AChE inhibitor work by hindersing the nucleophilic reaction on serine-203 (Ser203). Covalent AChE inhibitors with a carbamoyl group interact with the alcohol functional group in Ser203 at the esteratic active site of the AChE enzyme, forming an ester bond between these two compounds. As a result, Ser203 is carbamoylated, and the nucleophilic attack on the carbon in the acetic acid group of the ACh molecule will not occur when the carbamoyl group is attached. An example of this is rivastigmine (Exelon), a slow-reversible carbamate inhibitor, the covalent bond of which is difficult to hydrolyse by water (Colovic et al., 2013). This enhances the cholinergic effect by increasing the concentration of ACh. Rivastigmine is available as a transdermal patch (Dhillon, 2011).Chronic stimulating caused by a high concentration of glutamate can lead to cell death because of excitotoxicity. Excitotoxicity, caused by a high concentration of calcium, results in the cytoplasm. The two calcium ion extrusion mechanisms – sodium-potassium adenosinetriphosphatase (ATPase) and the calcium-sodium exchange process – become less active as the ATP level decreases. This leads to an exocytosis of vesicles containing neurotransmitter which is an excitatory neuron in the case of AD. If one portion of the brain becomes ischaemic, all the neurons there become hypoxic. Glutamate is released from the dendritic spines of presynaptic neurons and causes excessive activation of other neurons the calcium levels within those neurons increase and eventually neuronal death occurs, due to the high concentration of calcium. Memantine is “a receptor on synapses that binds the neurotransmitter glutamate and also binds its agonist NMDA (N-methyl-D-aspartate)” (Martin, 2015). This drug is considered a fast-off, uncompetitive voltage-dependent NMDA receptor antagonist (Danysz and Parsons, 2012) that can slow down neurodegeneration by reducing the ability of amyloid plaques or neurofibrillary tangles. The principal concept is to prevent excitotoxicity by blocking NMDARs, which were previously discussed. More importantly, memantine does not stop physiological neurotransmission entirely, as the drug does not react in instantly, calcium transmission still happened in a low amount. The fast-off property is effected by memantine changing the confirmation of NMDARs when the channel is closing, and then the receptor pushes the drug out off the channel.As AD cannot currently be cured, the significant problem in existing AD treatments is that all of the drugs used target the symptoms of the disease, not the disease itself. Both AChE inhibitors and memantine’s clinical use are limited by significant adverse effects and low efficiency. For example, dosage and patient condition are two factors that lower the effectiveness of AD treatment. Additionally, “peripheral cholinergic side effects are most notable for rivastigmine” (Casey et al., 2010). Although gastrointestinal adverse problems can be reduced by using a rivastigmine transdermal patch rather than a capsule (Rodda and Carter, 2012), this drug requires daily gradual dose escalation. Therefore, only a limited number of patients can be treated using this medication.Additionally, side-effects are common in many AD drugs. The serious side-effects of AChE inhibitor treatment can cause dysfunction to the patient’s body. The most common adverse effects of AChE are nausea, vomiting, diarrhoea, abdominal pain, and dizziness (Rodda and Carter, 2012). For example, Donepezil results in haematological and cardiac effects including anaemia, thrombocytopenia, and bradyarrhythmia, (Schneider, 2000). Bradycardia is one of the particular adverse events of concern, due to “cholinergic compounds having vagal tonic effects that may significantly lower heart rate” (Schneider, 2000). Myasthenia and respiratory depression are also particular concerns in AD drug treatment. Currently, in the UK, using cholinesterase inhibitors as an AD medicine remains outside current licence indications and guidance as per the National Institute for Health and Clinical Excellence (NICE) (Rodda and Carter, 2012). For the NMDA medication memantine, side-effects include constipation, dizziness, headache, hypertension, and somnolence (Rodda and Carter, 2012). The difficulty of treating AD lies in the fact that, once clinical signs of AD become evident, much of the CNS pathology is already well-established, and difficult to reverse.Alongside the development of basic research and animal models, an optimistic outlook can be observed in the form of academic and experimental breakthroughs. Treatments that address the pharmacological causative factors of AD does not yet exist. However, many potential disease-modifying therapies are currently being explored in pharmaceutical industries. The majority of current AD drug research is focused on developing disease-modifying therapies (Cuello, 2008) and accurate biochemical diagnostic markers.One of the most attractive therapeutic targets is an AD antibody. Two companies have reported new antibody drugs: Biogen’s aducanumab and Lilly’s solanezumab, both of which target amyloid-? protein, which is the main component of amyloid plaque. Aducanumab, which is a human monoclonal antibody, is injected during the early stage of AD patients. B cells are a type of white blood cell (WBC) that secretes antibodies and myeloma plasma cells, which are tumour cells of bone marrow. When these combine with the b cells, a hybridoma is formed. This is a unique parent cell that gives rise to antibodies known as monoclonal antibodies, which have monovalent affinity, and bind to the antigen. Aducanumab attacks aggregated forms of amyloid-?, which includes soluble oligomers and fibrillary aggregates. Clinical trial results show that “aducanumab penetrates the brain and decreases A? in patients with AD in a time-and dose-dependent manner.” (Sevigny et al., 2016) Solanezumab is another monoclonal amyloid antibody that has progressed to phase three clinical trials; unfortunately, they did not meet the primary endpoint of this phaseSerious side effects of existing drugs make us go deep into research and development in AD treatments. Although there is a vacancy of efficiency AD drug on the market today, research into therapies for AD is active. Researchers learn from the old drug research and development of new drugs or a combination of the two to reduce the side effects and increase efficiency, followed by antibody research have also made some progress, such as aducanumab which is mention above. There are also Electrical and Magnetic Stimulation treatments, which are also included in the potential future treatment of AD.