Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder of the brain and is considered the most common cause of dementia. It accounts for up to 70% of all dementia cases diagnosed according to current clinical diagnostic criteria. Dementia is an umbrella term describing a collection of symptoms that are caused by brain disorders. AD and dementia have become a global challenge with an overall age-standardised prevalence rate of between 5% and 8% (Burns and Waldemar, 2017). The estimated proportion of the general population aged 60 and over with dementia at a given time is between 5 to 8 per 100 people. The World Health Organisation (WHO) estimates that the number of people living with dementia worldwide is around 50 million, with nearly 10 million new cases every year. It is projected that the total number of people with dementia worldwide will reach 82 million in 2030 and 152 million in 2050 (World Health Organisation, 2017). Age is the strongest known risk factor for dementia, although it is not an inevitable consequence of aging. Some research has shown a relationship between the development of dementia and risk factors. These risk factors include physical inactivity, obesity, tobacco and alcohol use, diabetes and midlife hypertension (World Health Organisation, 2017). The symptoms characteristically include difficulty with memory, language, problem-solving and other cognitive skills such as thinking and behaviour which affect an individual’s ability to perform everyday tasks. These symptoms occur as the neurons in the brain that are involved with cognition are damaged or destroyed. As AD progresses, the neurons in other regions of the brain are also eventually damaged or destroyed, leading to complete degeneration of normal human functioning such as being unable to walk or swallow. In the final stages of AD, the individual is restricted to bed and requires full-time palliative care, ultimately leading to death (2018 Alzheimer’s disease facts and figures, 2018). Pathologically, Alzheimer’s Disease is characterised by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Ever since the discovery by german neurologist, Dr. Alois Alzheimer in 1906, neuropathologists have identified amyloid plaques and neurofibrillary tangles in the autopsied brains of people affected with AD, suggesting that those who have these pathologies, have the disease (Ramirez-Bermudez, 2012). Amyloid plaques are extracellular deposits of the amyloid beta protein (Aβ) in the brain parenchyma and cerebral blood vessels. In cerebral blood vessels, they are known as a cerebral amyloid angiopathy (CAA) or sometimes known as a congophilic angiopathy. Neurofibrillary tangles are composed of dissociated microtubules and hyperphosphorylated tau proteins that form insoluble twisted fibres (Anand, Gill and Mahdi, 2014). While these neuropathological features have been recognised, the intricacies of the causative mechanism have not been clearly defined. There are several hypotheses that attempt to explain causative mechanisms of this multifactorial disorder such as the cholinergic hypothesis, the Aβ hypothesis, the tau hypothesis and inflammation hypothesis (Kurz and Perneczky, 2011). The most influential model of AD pathophysiology is the Aβ hypothesis, also known as the amyloid cascade hypothesis (Hardy, 2009). This model is mainly based on the findings of the autosomal dominant variant of the disease. The amyloid precursor protein (APP) is usually cleaved by α-secretase. Instead, APP is processed by β-secretase and γ-secretase resulting in an imbalance between production and clearance of the Aβ peptide. This imbalance causes Aβ to spontaneously transform into soluble oligomers that can bind to fibrils, making an insoluble beta-sheet conformation which is eventually deposited in diffuse or compact plaques. It is predicted that the small soluble aggregates of Aβ are the major drivers of neuron and synapse loss and not actually the microscopically visible plaques (Jakob-Roetne and Jacobsen, 2009). This is further supported by a study from Nimmrich and Ebert (2009), where the toxic effects of small peptide complexes were observed on synapses and mitochondria. Extracellular Aβ deposits are associated with an inflammatory response which involves clustering of activated microglia and upregulation of acute phase proteins, cytokines and other inflammatory mediators. (Eikelenboom et al., 2006). However, it is not the number of amyloid plaques that represents the major cognitive decline but instead the amount of nerve cell and synaptic loss in the hippocampus and neocortex (Arendt, 2009, 2009). The neurodegeneration involves subcortical brain areas, including the basal forebrain (Schliebs and Arendt, 2006), the locus caeruleus (Weinshenker, 2008), and the dorsal raphe nuclei. The neurodegeneration of these areas creates a deficit of acetylcholine, norepinephrine and serotonin which contribute to the impairment of attention, memory, mood and behaviour. AD is diagnosed by conducting tests of memory, problem solving, attention, counting and language and performing brain scans such as CT, MRI or PET. However, AD can only be definitively diagnosed after death by linking clinical measures with an examination of brain tissue during an autopsy. There is currently no cure for Alzheimer’s Disease, nor is there a way to stop or slow its progression. However, there are treatments that can help with the symptoms. There is a prominent loss of cholinergic, noradrenergic, dopaminergic and GABAergic neurotransmission in AD (Breitner, 2003). Therefore, neurotransmitter-based treatment particularly targets neurotransmitter systems, in particular the cholinergic system to maximise the remaining activity in affected neuronal circuits. The currently available treatment strategies include Acetyl-cholinesterase Inhibitors (AChEI) and N-Methyl-D-aspartate (NMDA) receptor antagonists (Silvestrelli et al., 2006). Amongst all of the drugs that modify cholinergic neurotransmission, Acetyl-cholinesterase Inhibitors are the only class of drugs that have been cleared by regulatory authorities for symptomatic treatment of AD. The mechanism of action of these drugs is to slow the breakdown of Acetylcholine to prolong cholinergic neurotransmission. A patient who is treated early and persistently should show less evidence of behavioural, functional and cognitive deterioration over a period of time than one would expect in the absence of pharmacotherapy. Interestingly, humans have two types of cholinesterase’s, AChE and BuChE. The physiological role of BuChE is unknown, but levels of this enzyme have been shown to increase as AD progresses, whereas levels of AChE decrease (Cummings, 2004). Both of these enzymes are found in Aβ plaques and their inhibition with cholinesterase inhibitors may modify the deposition of Aβ, which is a key component of the pathophysiology of AD. There are three AChEI’s that are commonly used to treat patients with mild to moderate AD. These are: donepezil, rivastigmine and galantamine. Donepezil and galantamine are selective AChE inhibitors. Rivastigmine inhibits both AChE and BuChE from degrading ACh. Cholinesterase inhibitors are suggested for use in patients with mild to moderate AD, although a small benefit in patients with more advanced stage AD has been shown in some studies. (Doody et al., 2001; Cummings, 2004). The NMDA receptor antagonist that is used to treat AD is Memantine. It improves the signal-to-noise ratio of glutaminergic transmission and protects neurons from being overexposed to glutamate. This treatment will delay symptom progression over several months but have inconsistent effects on activities of daily living (Farlow and Pejovic, 2008) and a doubtful impact on some of the behavioural disturbances that are associated with AD (Grimmer and Kurz, 2006).
Alzheimer’s Disease is a complex condition and the pathogenic mechanisms of AD are still incompletely understood. It can be said with certainty that they involve complex relationships on cellular and sub-cellular levels that result in extreme neuron loss and synaptic destruction causing the degeneration of integrated higher brain functions. While there is no cure, there are some therapies that can make symptoms more manageable. Symptomatic treatment is the best part of the management currently. However, if the future it is hoped that there will be some exciting and incredible leaps in developing disease modifying approaches.
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