A Comprehensive Review on Causes

Introduction:

Alzheimer’s disease commonly abbreviated as AD is the most prevalent type of dementia. It is a progressive disorder causing degeneration and death brain cells. It was first described in 1907 (Albert et.al 2011). This was done by German physician and psychiatrist Alois Alzheimer who observed a patient who had developed an earlier than usual case of dementia. Following the death of the patient he then went ahead and carried out pathological studies on her brain. This disease is now the 6th leading cause of death in the USA and is slowly becoming a global concern as more and more new cases are reported. It is estimated that by 2020 the prevalence of the disease will have increased to 41.25 million (This figure includes both the early stages and late stages) (McKhann et.al, 2011). There is however no known cure for this disease despite the availability of several drugs which seem to be able to slow down the progression. People in the late stages of this disease require highly specialized care almost equivalent to those in a nursing home. This kind of care is very expensive (McKhann et.al, 2011). It is in this respect that we need to spend time to review the disease looking at its causes, symptoms, pathology, and ways of diagnosis, therapeutic treatment and drug targeting for this disease (Albert et.al 2011).

This disease which mainly manifests itself in severe forms in old age has its onset several years earlier. It progresses from mild cognitive impairment which takes a duration of about seven years, during which the disease is in the medial temporal lobe. It then moves to mild Alzheimer’s which takes a duration of 2 years. During this time the Panetal and Lateral temporal lobes are affected. It then moves to moderate Alzheimer’s where the disease now affects the frontal lobe. This also takes two years. The last stage is severe Alzheimer’s. This is stage when the disease spreads to the occipital lobe. (Bateman et.al, 2017) As the disease progresses over the years the following symptoms are associated with it. Its key symptom is a persistent and constantly worsening memory loss. This may involve frequent misplacement of items, inability to remember recent events, inability to acquire and retain new information, gradual loss of ability to perform routine tasks such as paying rent eating and bathing. The patient loses body coordination thus loosing balance. They are unable to recognize familiar people and objects such as forgetting names and appearances of family members and searching out for things that are directly in front of them (Musiek et.al 2015). The disease is also characterized by personality and behavioral changes which include mood swings, being irritable and aggressive, social withdrawal, wandering, failure to trust others, delusions and depression. These symptoms render a person unable to function at home and in the work place as they are unable to think, reason, multitask, remember important things or make decisions.

It is important to note that until now doctors have not been able to diagnose Alzheimer’s disease with certainty. This kind of diagnosis is only possible after the death of the patient when neurofibrillary tau tangles and beta amyloid deposits can be found in the brain. Despite this fact attempts must be made to try to rule out other types of dementia and find Alzheimer’s disease because of the serious health effects it poses (De Leon et.al, 2004). These attempts include review of the patient’s history and symptoms preferably conducted by a neurologist. This involves a review of thinking skills, language skills, personality changes, problem solving skills and the effect of the thinking problems on the patient’s life (Karlawish et.al, 2017) Doctors can also conduct interviews with friends or relatives of the patient in order to be aware of any changes in the behavior and cognitive skills of the patient under question. Laboratory tests are oftenly carried out so that other types of dementia can be ruled out. Brain scans can reveal an abnormal brain change and can also help in ruling out other causes of cognitive impairment such as stoke. Some of the technologies used in brain scans include Magnetic resonance imaging which uses radio waves and magnets to produce an image of the brain, computerized tomology which uses X-rays to obtain the cross sectional image of the brain. Positron emission tomography which uses radioactive tracers to identify brain regions which exhibit reduced metabolism (Frisoni et.al, 2017).

As persons age they are more at risk of having Alzheimer’s disease. This disease is however not a part of normal aging. People aged 65 years and above are at more risk than younger persons. After this age the risk doubles of Alzheimer’s disease doubles with an increment of every five years. A person is also at risk of developing the disease if an immediate family member like parents and siblings have suffered from the same (Luchsinger et.al, 2005) This is partially explained by the fact that APOE e4 gene, a variation of apoliprotein E gene is linked to increased risk of the disease. Persons with Down syndrome are at a higher risk since they have three copies of the gene responsible for creating beta amyloid, this resulting from having three copies of chromosome 21. (Lindsay et.al, 2002) Persons who have had severe and in most cases repeated head injuries are also at a higher risk of developing the disease (Reitz & Mayeux. 2014). Persons with health conditions such as diabetes, high blood pressure, high cholesterol levels, obesity, mitochondrial damage and heart diseases are also at a higher risk of Alzheimer’s disease. Poor sleep patterns also increase the risk of the disease. The presence of reactive oxygen species increase risk of the disease. More women generally suffer from Alzheimer’s disease as they age as compared to men. This can be associated with the fact that women generally live longer than men. (Barnes & Yaffe, 2011)

There are five known pathological hallmarks of Alzheimer’s disease. These are extracellular Peptide Amyloid Beta (Aβ) deposits sometimes referred to as Amyloid plague, acetylcholine deficiency, and intracellular aggregates of filamentous tau protein known as neurofibrillary tangles, neuroinflammation, and glutamate excitotoxicity (Hung & Fu, 2017).

A two-step proteolysis reaction caused by β-secretase and γ-secratase, (The two membrane bound proteins) enzyme complexes results in the formation of the peptide Amyloid beta from the amyloid precursor protein (APP) (Canu et.al, 2017) It is hypothesized that the accumulation of amyloid beta is the initial cause of AD. β-secretase (BACE) inhibitors can be used to inhibit the Amyloid beta production (Hung & Fu, 2017). This inhibitor is a type 1 transmembrane aspartic acid protease. It is able to interfere with the amyloid cascade in the upstream stage. It thus modulates Amyloid beta production. The production of β-secretase (BACE) inhibitors has however faced a lot of challenges with most potential drugs failing in clinical phase i due to poor blood-brain barrier penetration, liver toxicity and non-bioavailability. (Canu et.al, 2017) Despite these setbacks E2609, AZD3293, CNP520, JNJ-54861911, third generation BACE 1inhibitors have shown satisfactory pharmokinetics in the studies being carried out currently and are good candidates for use as drugs. (Hung & Fu, 2017) Another potential inhibitor to be used is γ-secretase. This is a protease inhibitor which has four units which include, presenilin (PEN-1), nicastrin (NCSTN), presenilin enhancer 2 (PEN-2) and anterior pharynxdefective 1 (APH-1). Each of these subunits has a potential of being used to stop Amyloid beta production or to increase its clearance from the brain. Semagacestat and avagacestat γ-secretase inhibitors were however discontinued in phase iii and ii respectively due to worsening symptoms and serious side effects such as cerebral micro bleeds, skin cancer and glycosuria which is dependent on dose. NIC5-15, pinitol, a cyclic naturally occurring sugar alcohol which can modulate γ-secretase and thus inhibit Amyloid beta production is the current drug candidate in phase ii trial. Passive and active immunotherapy can also be used to clear Amyloid beta. These target the use of vaccines, both active and passive ones. The major challenge faced with this has been the inability to safely translate the vaccines into humans. The synthetic vaccine AN-1792 Alzheimer failed to be successfully translated because it reported development of meningoencephalitis in 6% of the patients under treatment. (Hung & Fu, 2017). Passive and active immunotherapy also targets the possibility of use of antibodies to lower amyloid beta. Solanezumab is an antibody now in phase iii trial for mild Alzheimer’s disease with its target being the mid region of Amyloid beta. The human monoclonal antibody (BIIB-037 or aducanumab) is currently the strongest hint of clinical benefits of an agent targeting amyloid. This emerged from the screening of B-cell clones which were obtained from healthy old people. The 10mg dose of this drug substantially reduced PET amyloid levels from six to twelve months with the only adverse effect being transient amyloid-related imaging abnormality-edema in only 20% of the test population. This is a great potential for the development of a therapy for Alzheimer’s disease through targeting amyloid beta (Selkoe & Hardy 2016)

One of the key features of AD the aggregation of hyperphosphorylated tau proteins. This affects neurons and results into cell death when the soluble tau aggregates assemble causing the formation of paired helical filaments which result in the formation of neurofibrillary tangles. The consideration of this pathway is important as there is a direct link between Alzheimer’s disease and the tau tangles (Barret et.al, 2017). (Hung & Fu, 2017) It is possible to target these neurofibrilliary tangles using tau stabilizers. These stabilizers work by enhancing microtubule stabilization. Several of these including Epothilone D, TPI 287 have failed to reach the clinic due to toxic side effects that they have been reported to have in cases of mild to moderate Alzheimer’s disease. The use of tau aggregation inhibitors is another means that has been targeted inorder to deal with Alzheimer’s disease. Methylene blue derivatives such as Rember have been shown to stop tau protein aggregation. This first generation inhibitor has however failed because of side effects such as diarrhea, dizziness, causing patients to fall, pain during urination, and urinary agency. Second generation methylene blue indicator TRx0237 (LMTM) has failed to produce any credible inhibition. Attempts have also been made to use active immunotherapy to target clearance of tau tangles. This has involved the use of antibodies with high affinity against phosphorylated tau. (Hung & Fu, 2017)

There is a hypothesis that the decline of acetylcholine is responsible for the progressive loss of cognitive function. There have been several attempts to correct acetylcholine levels as a way to deal with the Alzheimer’s disease. The first attempt was the use of tachrine a reversible acetylcholinesterase Inhibitor (AChEI) in 1993. This however did not work as the drug was found to be toxic to the liver (Hung & Fu, 2017). This made it necessary to invent other acetylcholinestearase inhibitors which included donepezil, galantamine, and rivastigmine. These drugs are currently in use for the management of Alzheimer’s disease. These drugs have been able to reduce the activity of acetylcholinestearase and hence slow down Alzheimer’s disease by slowing down the loss of cognitive function (Hampel et.al, 2018). The expression of 5-HT6 receptor in the hypothalamus and cortex impairs serotonergic neurotransmission leading to the development and progression of Alzheimer’s disease. Thus the use of 5-HT6 receptor antagonists stands a chance to improve the neurotransmission of acetylcholine. (Hung & Fu, 2017) This has indeed been effected in an oral dose of idalopirdine (Hung & Fu, 2017). This drug showed safety and efficacy in clinical trials phase ii but had failed in phase iii clinical trials. The failure of idalopirdine in phase iii trials led to the development of intepirdine currently in phase iii trial. These two drugs target the improvement of memory in patients with mild to moderate Alzheimer’s disease (Hung & Fu, 2017) The two drugs can be used together with idalopirddine being used in phase ii and interpirdine being used in phase three to enhance cognitive function of patients in the mild stages of Alzheimer’s disease. They are however still in clinical trials. Another strategy to deal with acetylcholine levels is the use H3 receptor antagonists (Hampel et.al, 2018). This is because histamine receptors are widely distributed in the central nervous system and affects both histamine and acetylcholine neurotransmission. The H3 antagonists were however found to be ineffective in treating cognitive dysfunction following the failure of GSK239512 and ABT-288 in clinical phase ii trials. Despite the potential ineffectiveness of these drugs, SUVN-G3031 a histamine antagonist is in phase I trials with the hope that it can be potent for improving acetylcholine levels. The α7 nicotinic acetylcholine receptor (α7nAChR) agonists have also been targeted as means of enhancing acetylcholine response. This is because α7nAChR is dispersed in the hippocampus, and the frontal and prefrontal cortices. It is also involved in memory, ability to acquire knowledge, perform calculations, to learn languages, to think and to remember things (Hung & Fu, 2017).The α7nAChR is a carrier and binder of Amyloid beta and can thus inhibit neurotoxicity through autographic degradation. Encenicline is the first α7nAChR agonist to be produced. Together with acetylcholine they are able to improve cognitive function of those suffering from Alzheimer’s disease. The challenge with this α7nAChR agonist is that it was found to have gastrointestinal side effects in phase three of its clinical trials and was therefore found unsafe to be used.

Glutamate cytotoxicity is linked to Alzheimer’s disease as causes vulnerability of neurons in a manner identical to the situation in Alzheimer’s disease. Memantine an N-methyl-D-aspartate (NMDA) receptor is clinically used to prevent the glutamine mediated excitocytotoxicity on the neurons. This is the only drug used for this purpose and has been in use since 1989. Riluzole a drug suspected to be able to reduce glutamine concentrations in the hypothalamus is in phase ii of clinical trials. The investigation is on whether it has beneficial cognitive effects especially for mild Alzheimer’s disease. (Hung & Fu, 2017)

astrogliosis and other signs related to inflammation. The hyperactivation of micrologia in Amyloid plagues is highly linked to the progression of Alzheimer’s disease. Microglial activation inhibitors have been investigated as a possible inhibitor for neuroinflammation. Azeliragon has been shown to reduce Amyloid beta levels in the brain and improve cognitive function. This drug is currently in phase iii of clinical trials. Other drugs such ibuprofen and flurizan which are used as anti-inflammatory agents have however failed to improve cognitive performance in clinical trials. More potential drugs are still under clinical trials with a hope of finding a suitable drug. (Canu et.al, 2017)

New targets for the treatment of Alzheimer’s disease are Intravenous immunoglobulin (IVIG), Calcium channel blocker and nasal insulin. Nasal insulin is a targeted therapy since brain areas affected by Alzheimer’s disease show reduced levels of insulin and a resultant increase in insulin receptors. The intranasal insulin improves memory, cognitive function and regulates amyloid beta in early cases of Alzheimer’s disease. Nilvadipine a calcium channel blocker has shown potential reduction of Amyloid beta levels. (Hung & Fu, 2017)

Conclusion

More and more people are being diagnosed to have Alzheimer’s disease after the age of 65. This disease is second only to cancer when it comes to the kind of care the patients need. With the increased life expectancy in the world it is important that a cure be found for this disease. As discussed above one of the key challenges drug discovery has faced is the presence of side-effects to most of the effective drugs. There is therefore need to find ways of dealing with the side effects which may involve the administration of drugs in combinations.

References

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