Introduction

The brain is a significant and complex organ with a vast array of roles necessary for sustaining human life. Some of these include cognitive functions, homeostatic regulatory responsibilities, motor controls, and sensory information reception. While the human brain has numerous capabilities essential to life, a wide range of neurological disorders can impede these, causing a variety of potentially fatal diseases, such as Alzheimer's disease.

German physician Dr. Alois Alzheimer first described Alzheimer's disease as presenile dementia in 1906. Now known to be a progressive neurodegenerative disorder, Alzheimer's disease is the most common form of dementia, accounting for nearly 35 million cases globally (Martorelli, et al.). In the United States today, it is speculated that someone develops Alzheimer's disease every 66 seconds, however in 2050, a new case of Alzheimer's is expected to develop in as little as every 33 seconds (Alzheimer's Association). Subsequently, since Alzheimer's disease has become much more widespread, it has also become much more fatal. As of 2014, in the United States alone, the disease was reportedly responsible for approximately 85,000 deaths. Moreover, during the years 2000 to 2013, the number of deaths caused by Alzheimer's disease increased by over 71%, while mortality caused by stroke, heart disease, and prostate cancer actually decreased by 23%, 14%, and 11%, respectively (Alzheimer's Association). However, it is important to suggest that these mortality statistics may be greatly underestimated since death certificates may list other complications as causes of death, rather than the underlying Alzheimer's disease.

Additionally, a key aspect of the surging prevalence of Alzheimer's disease as a fatal disorder is that it is only intensifying with increasing longevity in humans. For example, in his article Pathogenesis of Alzheimer's disease, Dr. Russell Swerdlow, the Director of the University of Kansas Alzheimer's Disease Center and the KUMC Neurodegenerative Disorders Program, references a survey of brains from persons over the age of 85 that all showed evidence having at least some degree of Alzheimer's disease. He states that therefore, it is worth considering that at some point in the aging continuum, Alzheimer's disease ceases to become a disease because it becomes a norm.

Thus, as the facts and statistics stated above may imply, Alzheimer's disease is becoming a widespread disease characterized as much more than the memory loss commonly associated with it. Unfortunately, however, the diagnosis of Alzheimer's disease is primarily reliant on observations of cognitive and functional decline (Martorelli, et al.). These symptoms include: agnosia, the loss of perceptual ability regarding the interpretation of sensory perceptions; apraxia, the inability to understand the meaning or appropriate use of things; and dysphasia, the failure to arrange words in a meaningful manner (Martone and Piotrowski). Therefore, due to the complexity and extent of the neurological deficits that which it causes, Alzheimer's disease is typically terminal once it has finally been diagnosed. In addition to its inability to be diagnosed through practical medical testing, Alzheimer's disease is even more so fatal as a result of the uncertainty behind its physiological causes and the lack of a known cure.

Causes

An early feature of Alzheimer's disease is synaptic loss that renders neurons dysfunctional and prone to irreversible death, ultimately precipitating the severe brain atrophy and cognitive impairment observed in later stages of the disease (Seddighi, et al.). Simply put, Alzheimer's disease causes the volume of the brain the shrink considerably. However, there are several hypotheses as to why this happens.

The most well-known theory, the amyloid cascade hypothesis, has been the mainstream concept underlying Alzheimer's disease research for more than 20 years (Kametani and Hasegawa). Usually resulting from genetic mutations on chromosome 21, this hypothesis states that various pathological changes occur in response to abnormally increased concentrations of beta-amyloid protein (Widmaier, et al). This protein is derived from its much larger precursor, the beta-amyloid precursor protein (APP), by two proteases, beta-secretase and gamma-secretase. Specifically, a mutation in two amino acids (lysine and methionine mutated to asparagine and leucine) of APP adjacent to the beta-secretase site is known to increase beta-secretase activity and thus, beta-amyloid protein production (Martone and Piotrowski).

In addition to mutations affecting chromosome 21, the specific mutations of the genes presenilin 1 and presenilin 2 associated with chromosomes 14 and 1, respectively, also result in the increased production of the beta-amyloid protein. Alternatively, this protein is the much larger and more pathogenic version, which is known as the beta-amyloid protein 42 (Martone and Piotrowski). Because of this, the two presenilin mutations usually trigger an early onset of Alzheimer's disease, and presenilin 1, specifically, can even occur in patients as early as age 30. Therefore, it can be inferred that Alzheimer's disease caused by mutation of the presenilin 1 gene is characterized as being far more malignant than the other forms of the disease. Not only is this due to its extraordinarily early onset, but it also is the result of its increased aggression characterized by the abundance of amyloid plaques in more detrimental regions of the brain, such as the cerebellum (Martone and Piotrowski).

As stated previously, the increase in beta-amyloid protein production results in a triad of of pathological changes, including the formations of senile plaques, amyloid angiopathy, and neurofibrillary tangles. To elaborate, senile plaques consist of amyloid deposits surrounded by dystrophic neurons, while amyloid angiopathy is the presence of the same deposits within the brain vasculature. Neurofibrillary tangles, on the other hand, are simply tangled fibrillary protein aggregates within nerve cells of the brain, but, however, these components have drawn quite a bit of attention lately (Martone and Piotrowski).

Some scientists have begun to develop a new hypothesis focusing on the neurofibrillary tangles as the basis of their Alzheimer's research. Neurofibrillary tangles specifically contain abnormally configured and excessively phosphorylated tau protein. This is significant because in most differentiated cells, tau is generally unphosphorylated and is responsible for associating with microtubules to form a permanent cytoskeleton (Swerdlow). The human tau gene is localized on chromosome 17, and as the result of mRNA alternative splicing, it has six known isoforms expressed in the adult human brain. In other neurodegenerative disorders, such as frontotemporal dementia, mutations associated with the tau gene result in either protein accumulation, which causes neuronal degeneration, or impairment of microtubule regulation, ultimately leading to extensive cell damage (Kametani and Hasegawa). Furthermore, recent positron emission tomography (PET) studies have shown that the spatial patterns of tau tracer binding are closely linked to the patterns of neurodegeneration and clinical presentation in Alzheimer's disease patients (Kametani and Hasegawa). In addition, tau lesions in the brain have also been shown to occur earlier than beta-amyloid protein deposits. Therefore, it is believed that Alzheimer's disease progression is more reliant on tau pathology than amplified beta-amyloid protein production (Kametani and Hasegawa).

Somewhat humorously, there has been a long-standing debate regarding the significance of the pathological findings in Alzheimer's disease. This argument has questioned whether beta-amyloid-protein-associated pathology or the tau-protein-associated pathology is the primary lesion in the disease, which therefore has divided investigators into ""baptist"" and ""aoist"" camps (Martone and Piotrowski). For example, on one hand, some may argue that the amyloid plaques are a result neurodegenerative processes, such as normal aging or neurofibrillary tangle-associated neuronal degeneration, rather than their cause. On the other hand, however, others may argue that there have been no direct links between the genetics of Alzheimer's disease and the tau protein, even though a mutation has been identified in tau when its associated with non-Alzheimer's dementia, or frontotemporal dementia (Martone and Piotrowski).

Nevertheless, outside of this debate an additional theory, the mitochondrial cascade hypothesis, has recently arose. This idea assumes that similar physiological mechanisms underlie both Alzheimer's disease and common brain aging. More importantly, it postulates that since Alzheimer's disease mitochondrial dysfunction is systemic, it cannot be a consequence of neurodegeneration (Swerdlow). In contrast to the amyloid cascade hypothesis, which is based on studies of rare, autosomal-dominant mutants, this proposal looks to determine the causes of common late-onset, sporadic Alzheimer's disease.

In this model, the makeup of an individual's electron-transport chain is inherited and gene-specific. The chain sets basal rates of reactive oxygen species (ROS) production, which therefore determines the rate at which mitochondrial damage occurs. As a result, oxidative mitochondrial DNA, RNA, lipid, and protein damage amplifies ROS production and triggers three events (Swerdlow and Khan). First, it signals a reset response in which cells respond to the elevated ROS by generating the beta-amyloid protein, which further impedes mitochondrial function. Then, it prompts a removal response in which compromised cells are disposed of through apoptosis mechanism, and finally, it generates a replace response in which neuronal progenitors unsuccessfully attempt to re-enter the cell cycle, which results in aneuploidy, tau phosphorylation, and neurofibrillary tangle formation (Swerdlow and Khan).

Ultimately, the probable causes of Alzheimer's disease all converge at one main idea: Alzheimer's disease is the direct result of neuronal degeneration and decreased synaptic density due to some sort of protein accumulation within the tissues of the brain. Therefore, due to neuronal death, there is a widespread decline in various neurotransmitter-containing cell bodies of the brain. However, the most consistent losses throughout the progression Alzheimer's disease are that of the cholinergic neurons of the basal forebrain (Mufson, et al). Despite this congruence, however, understanding the pathophysiological mechanisms that drive neurodegeneration, and therefore the subsequent acetylcholine deficits, in Alzheimer's disease is crucial for rationally designing neuroprotective agents capable of preventing the disease progression (Coimbra, et al.).

Treatments

Currently, the treatment options available for patients with Alzheimer's disease are primarily palliative options that only address and temporarily alleviate symptoms of the disease. Some of the most common treatment options include acetylcholinesterase inhibitors, such as donepezil, rivastigmine, galantamine, and tacrine, to name a few (Martone and Piotrowski). By inhibiting acetylcholinesterase, these agents therefore inhibit the degradation of the neurotransmitter acetylcholine, which is commonly reduced in individuals with Alzheimer's disease due to neuronal degeneration (Widmaier, et al.). In addition, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, are also commonly prescribed in order to limit any inflammatory responses in the brain that may have been caused by any neurotoxic effects of the accumulation of the beta-amyloid protein (Martone and Piotrowski).

Furthermore, because of the limited effects of pharmacological treatments, the use of psychological and psychosocial interventions has become increasingly popular in recent years. This method, known as cognition-focused intervention is commonly partitioned into three separate approaches: cognitive stimulation (CS), cognitive training (CT), and cognitive rehabilitation (CR). In short, CS aims to enhance cognitive function through participation in a set of activities that engage mental processes, CT aims to improve specific cognitive functions through a set of standardized tasks with guided practice, and CR aims to address the impact of cognitive impairment of everyday functional ability in order to reduce disability and improve functioning in specific activities of daily living (Oltra-Cucarella).

More importantly, in order to better the lives of those afflicted and to decrease the overall mortality rate caused by Alzheimer's disease, research on new possible treatments is underway. For example, several groups of researchers worldwide are actively attempting to discover and develop beta-secretase inhibitors in order to limit the proteolytic processing of APP that subsequently produces beta-amyloid protein (Coimbra). Thus, by inhibiting the accumulation of this protein, these potential cures could stop the progression of Alzheimer's disease in its tracks. As a result, not only would this hypothetical cure improve the quality of life for those afflicted with Alzheimer's disease, but it would also increase the chance of prolonged survival.

Conclusion

Although Alzheimer's disease was first characterized in 1906, we, as humans, still have much to learn about the neurodegenerative disorder, even over 110 years later. Despite having a plethora of possible genetic causes, this disorder is generally classified as a progressive neurodegenerative disease. On the surface, Alzheimer's disease seems as though it is simply portrayed as memory loss due to a net shrinkage in brain volume. However, this is far from the truth. Alzheimer's disease is characterized by neurological degeneration and degradation caused by protein accumulation, whether it be beta-amyloid plaques or tau protein. As a result, this disease is associated with a variety of cognitive deficits, including agnosia, apraxia, and dysphasia, and it typically results in fatality. In summary, Alzheimer's disease research is incredibly significant to the lives of over 30 million people affected worldwide, making it one of the leading causes of death across the globe.

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It effects approximately 5.5 million Americans and is the sixth leading cause of death in elderly individuals. The disease is caused by a plaque formation of amyloid beta (A) in the brain. Currently, there is no cure for Alzheimer's disease however there are five FDA approved drugs to slow the progression of Alzheimer's disease.

Research into this disease has conventionally focused on the CNS, however, several peripheral and systemic abnormalities are now understood to be linked to AD. This has led to pursuit of understanding how altercations can contribute to AD and the creation of therapies and treatments to prevent them from occurring. As, dementia carries significant implications for patients, their families, and our society, it is imperative to determine the cause and pathway of this disease. More research focused on finding and understanding what triggers the initiation of A plaque production in the brain can lead to the discovery of a treatment for this condition.

An imbalance between the production and clearance of A is an early, an often initiating, factor in Alzheimer's disease. Previous studies focused on targeting amyloid-A formation as a hopeful treatment of Alzheimer's disease. One study attempted to regulate amyloid beta formation via immunotherapy. Amyloid-A targeting antibodies were used to prevent the formation of amyloid beta plaques, a hallmark condition of Alzheimer's disease. Mouse models were used to study two different antibodies against amyloid beta formation. Results indicated a decrease in A production, an increase in hyperactivity in the cortical area, and persisting neuronal dysfunction. The increase in hyperactivity indicated neuronal synchrony, a positive indication, and so, research was redirected to finding a treatment for the neuronal dysfunction. An experiment with monoclonal antibody, 3D6 and mice resulted in a decrease of A formation in the brain, also a positive indication. Research focus was then shifted again to determine whether if neuronal dysfunction could be treated prior to plaque formation, in the earlier stages of Alzheimer's disease. Increased hyperactivity was observed upon administration of 3D6 antibody to the mice, this indicated that antibody 3D6 exhibited a pro-excitatory effect that is dependent on the over expression of APP. Results also showed that mice treated for 5 months with exhibited reduced amounts of amyloid plaque production however this amount of reduction was less than what was observed compared to treatment with 3D6. Treatment with 3D6 provided a consistent affect of reduced aggravation. A 3-month study with antibodies to see if they also provided a consistent affect was performed.1 Results implied an increase in hyperactivity in the cortical area, but overall had no large impact on treatment performance. A conclusion was drawn that the reduction in amyloid beta plaque formation contributes to the aggravation of neuronal impairments. An additional study based on the role inflammation on the amyloid-antibodies responsible for hyperactivity was performed. Results demonstrated that inflammatory reactions did not affect levels of, nor had a role in the level of hyperactivity observed in the cortical region of the brain. The compilation of the studies concluded that the treatment of amyloid beta plaques with antibodies to A did not treat neural dysfunction but in fact worsened it. Further research, investigate to the repair of neuronal dysfunction needs to be performed.

BRCA1 has been determined to be central to learning and retaining memories. Gladstone researchers theorized that the cycle of DNA damage and repair in the brain is what facilitates the learning process.5 Decreased levels of this protein is exhibited in patients with Alzheimer's disease and leads to degeneration of cognitive function, which is a hallmark symptom of the pathology. Amyloid beta plaque formation can be associated with proteins such as BRCA1 and presenilin 1 expression, which would explain why neural dysfunction is present despite the inhibition of amyloid beta plaques and an increase in hyperactivity in cortical regions of the brain. This also reaffirms previous studies suggesting that impairment of neurons involved in cognitive processing can be present despite significant increases in hyperactivity and hyperexcitation in the cortical regions. This research provides insight as to how to stop the formation of amyloid beta plaques and also creates a foundation into why neuronal dysfunction is still present.

Intracellular tau protein tangles have also been indicated as a biomarker in the molecular pathogenesis and studies have indicated that AD is most likely an amyloid-enabled tauopathy and amyloid plaque production defines the stage of the disease.4 This is a significant finding because Tau's function is in the assembly and stabilization of microtubule structure. Studies based on the role of tau in neurodegeneration presents a therapeutic target for the pathology in addition to the measurement of amyloid-A plaques.

Other studies have focused on alterations of local neuronal circuits, due to amyloid plaques, and the role they play in Alzheimer's disease. Soluble A oligomers and amyloid plaques alter neuronal circuits and other networks by disrupting the balance of synaptic excitation and inhibition (E/I balance) in the brain. It was discovered that hyperactivity in cortical regions precede the formation of amyloid A plaque formation and could be the reason neuronal dysfunction persists despite inhibition of A plaque formation. Therapies that can correct the E/I balance during the extended early phase of AD may prevent neuronal dysfunction, cell loss and cognitive impairments associated with later stages of AD.

Moving forward we can expect a shift in focus, prioritizing intervention at the synaptic level prior to neuron degeneration is promising in the study of Alzheimer's disease and prevention. Identifying signals of declining synaptic health is vital to establishing measurable biomarkers to help identify the onset of AD. Biomarkers currently being researched are amyloid beta and tau proteins, however a note of importance is placed on identifying reliable early detection methods because early diagnosis gives the patient access to treatments to slow the progression of neuronal degeneration. This can provide retention of cognitive abilities, a better quality of life and a longer survival period after diagnosis.

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