Neurodegenerative Diseases: A Study of the Diagnostics, Risk Factors and Treatment of Alzheimer’s Disease

Abstract

Progressive neuronal degeneration is a classic hallmark of many neurodegenerative diseases. The degenerative process is characterized by misfolded proteins, calcium deregulation and inflammation [11]. Even though such pathologies have been identified, they are often overlapping with other neurodegenerative diseases, making it difficult to pinpoint diagnosis [13]. In addition, there are several factors that can exacerbate neurodegenerative diseases, such as stress, hypertension, depression, diabetes and low physical activity [5]. This review will focus on the pathology and risk factors of AD, as well as a discussion of recent advances in diagnosis and treatment. 

Introduction

It is estimated that nearly 6 million people in the United States are living with Alzheimer’s disease (AD). Statistically, 1 in 10 people over the age of 65 have AD and 1 in 3 people over the age of 85 have AD. The number of people with AD is likely to double by the year 2060 and is currently the 6th leading cause of death in the United States [26]. 

AD is also the most common cause of dementia. Dementia is a condition whereby cognitive function and cognitive failure are impacting daily living. AD causes dementia by decreasing the function of the nerve cells; however, there is no definitive cause for why the nerve cells are not functioning as well as they previously were [27]. Given the current research, the cause of AD is multifactorial, meaning that there are many factors contributing to the onset, progression and pathology of the disease. Damage to the neurons is thought to be the most common cause but there is also a genetic susceptibility. There are also some environmental factors that may play a role in AD, such as diet and infection [7]. There are some sympathetic drugs given to alleviate the symptoms with AD, such as, inhibitors to cholinesterase enzymes and antagonists to N-methyl d-aspartate (NMDA). However, there are no therapeutics to effectively cure the disease or effectively target the underlying biological processes of the disease [15].

Primary Characteristics of the Disease

Molecular Characteristics.

AD is characterized by having aggregates of protein called plaques. The plaques are amyloid beta deposits. Amyloid beta is formed when a protein called amyloid precursor protein is improperly cleaved by two enzymes: gamma and beta secretase. When amyloid precursor protein is normally cleaved (by the same enzymes), it leaves a soluble portion of amyloid beta that does not contribute to any neurotoxic effects. However, when it is cleaved incorrectly it leaves an insoluble form of amyloid beta. Amyloid beta tends to misfold and stick to itself, forming insoluble protein oligomers. These oligomers will then bundle together to form large fibrils that deposit in the brain as plaques. These deposits decrease the plasticity and communication between synapses, which could inhibit the production and retrieval of memories [13].

AD is also characterized by having neurofibrillary tangles in the brain that are made up of a protein called tau. In a healthy brain, tau helps to stabilize the microtubules. Microtubules stabilize the cytoskeleton of the neuron. However, in AD extra phosphate groups are attached to tau, causing it to separate from the microtubules. When tau is detached from the microtubules, it acquires an abnormal shape which congregates towards the cell body of the neuron – eventually killing the neuron [11].  

Tau not only affects the cytoskeleton but also contributes to mitochondrial dysfunction. Mitochondrial dysfunction has been observed in AD and has demonstrated a critical role in AD models and the pathogenesis of the disease [11]. Tau phosphorylation and amyloid beta can affect the efficiency of the mitochondria. For example, tau decreases the activity of Complex I – which affects ATP production and consequently the function of the mitochondria. Amyloid beta affects the mitochondria through the amyloid precursor protein [11]. For example, both amyloid beta and amyloid precursor protein disrupt the electron transport chain by localizing themselves in the mitochondrial membrane – which is critical for the processing oxygen used for cellular respiration. Localization of amyloid beta and amyloid precursor protein increases the reactive oxygen species production causing mitochondrial damage [24]. 

Cellular Effects.

Microglia represent about 10% of all the cells in the nervous system [26]. In a healthy neuron, microglia are immune cells by clearing out waste and by pruning synapses. They also consume amyloid beta by phagocytosis, in which a cell uses its plasma membrane to engulf a large particle. Since microglia are macrophages, they represent one of the first lines of cellular defense against injury and pathogens in the brain. They are also in a resting state under healthy conditions. However, if microglia get overstimulated, they can start to release too many inflammatory cytokines that can damage surrounding neurons. They can also phagocytose synapses which leads to neuronal death, leading to more brain loss. [26]

Astrocytes represent the most abundant type of cell of the central nervous system. Astrocytes constitute a star shaped morphology and are important for protection and differentiation of neurons. They also have other important roles such as oxidative stress regulation, ion homeostasis, synaptic remodeling, etc. Astrocytes have an important role in the permeability and health of the blood brain barrier as they are proximal to blood vessels and the interactions between endothelial cells. However, in Alzheimer’s disease, astrocytes can promote neurodegeneration by releasing inflammatory cytokines – which promote the formation of amyloid beta and can also compromise the blood brain barrier [26].

Organ System Characteristics.

The loss of synapses results in memory impairment – which is the most common symptom of AD.  Synaptic damage to the neocortex and limbic system is observed in the early stages of AD. The neocortex is part of the brain’s cerebral cortex, where it is responsible for perception, thought, attention and episodic memory. The limbic system is involved in our behavior and emotional responses [15]. Damage to synapses of the neuron affects the transport along the axon, which promotes oxidative stress and damages the mitochondria. These processes lead to further dystrophy of the neuron which impacts memory loss beyond the normal amount in aging [24].

Parts of the brain affected by the biochemical pathology of AD (amyloid beta plaques and neurofibrillary tangles), in the early stages, are the perirhinal and entorhinal cortex, both located in the medial temporal lobe. The perirhinal cortex is associated with visual spatial memory which affects familiarity and recollection of an individual. The entorhinal cortex is associated with memory and the association between different events. Pathological damage to these areas is reflected in the early stages of AD when patients start to forget names and their environment [13].

Pathogenesis and Hypotheses of AD

The definitive cause of AD has not been defined. There have been multiple hypotheses that have attempted to explain the cause of AD such as the amyloid cascade hypothesis, tau hypothesis or the calcium hypothesis. The amyloid cascade hypothesis has been the mainstream hypothesis governing AD research. This hypothesis assumes that the accumulation and deposition of amyloid beta is the primary cause of AD. The tau hypothesis assumes that the pathology of AD is governed by hyperphosphorylated tau in the neuron [33]. The calcium hypothesis of AD examines the alterations in calcium signaling pathways that are responsible for the pathology of AD [34]. However, there hasn’t been an accepted explanation for the ultimate cause of AD. Instead, there are multiple factors that can increase the chance of developing the disease such as age, genetics and some environmental factors. Environmental factors are up to debate as to whether they affect the onset of the disease; nonetheless, there has been correlation between some environmental factors and AD [15].  

Age

Age is the most common risk factor for developing AD. As the brain ages there is loss of synapses, brain volume and brain weight. These factors help to contribute to normal memory loss as one ages. However, patients with Alzheimer’s Disease experience memory loss beyond the normal memory loss of aging, losing their ability to be independent. For example, patients with AD forget information that they could remember readily previously. They start to have trouble finding words and solving-problems. These patterns of forgetfulness and other issues also start to become constant in their lives. This is different from normal forgetfulness, in which we all forget details; however, it is not to the point where others are starting to notice our forgetfulness and it is not interfering with daily tasks [30].

Genetics

There is genetic susceptibility to AD; however, these genes do not cause the disease (not deterministic). Rather, they just increase the risk of developing the disease. These genes include Amyloid Precursor Protein, Presenilin-1, Presenilin-2, Apolipoprotein E, Estrogen Receptor Gene [15].

Amyloid Precursor Protein (APP) is located on chromosome 21 and is a type I transmembrane protein. When it is cleaved by gamma or beta secretases, it releases amyloid beta. There have been 31 mutations associated with the APP genes and 25 of those were related to AD – which caused an abnormal amyloid beta accumulation. Presenilin-1 and Presenilin -2 are located on chromosomes 14 and 1. These proteins are very similar to each other in nature except for their hydrophilic region and their N-terminus. Presenilin-1 helps to promote the formation of Amyloid beta from APP by activating gamma secretase. Presenilin-1 mutations are more common than Presenilin-2 mutations; nonetheless, Presenilin-2 can also increase gamma secretase activity, leading to a greater amount of amyloid beta formation [7].

Apolipoprotein E is a glycoprotein located on chromosome 19.  It is highly expressed in brain astrocytes and the liver: playing an important role in myelin production and the metabolism of fats. Apolipoprotein E plays a crucial role in depositing amyloid beta and is associated with vascular damage in the brain – leading to AD pathogenesis. These genetic factors seem to support the amyloid cascade hypothesis of AD, in which one assumes the primary cause of AD is because of amyloid beta deposits [15].

Interestingly, one genetic factor that doesn’t follow the amyloid cascade hypothesis is the Estrogen Receptor Gene. The estrogen hormone activates estrogen receptors and causes hormonal changes. AD cases are mostly women. This could be because of these genes getting activated differently in women. Hormonal and other genetic variants, like Apolipoprotein E, could cause this increased risk in women [15].

Environmental Factors

Environmental factors pose some questions when it comes to how much of a role they play in increasing the risk of AD. Nonetheless, these factors have been associated with AD and should be considered when looking at the onset of the disease. 

Pollution

The six air pollutants that pose significant danger to human health include nitrogen oxides, carbon monoxide, particulate matter, lead, sulfur dioxide and ozone. Air pollution has been linked to an increase in amyloid beta formation, oxidative stress and inflammation in the brain. These processes can help to speed up neurodegeneration leading to a higher probability of developing AD. Using cellular and animal models, researchers have found that an excessive exposure to air pollutants can result in damage to the frontal cortex region. Damage to the frontal cortex is observed in patients with AD [7, 15].

Metals

Aluminum can be found in the cosmetics industry, processed foods, medical preparations, medicines and in various other industries. When aluminum congregates in the cortex and cerebellum of the brain it can interact with different proteins. These interactions can cause protein misfolding and hyperphosphorylation of tau. Lead has been observed with increasing the protein expression of beta-secretase, which increases amyloid beta formation from APP. Both lead and aluminum can readily cross the blood brain barrier which makes it easy for the metal to exert their neurotoxic effects on the brain, increasing the susceptibility to developing AD [15].

Diet

Deficiencies in folate, vitamin B12 and vitamin D may cause a decrease in cognitive function. High amounts of saturated fatty acids are also associated with an increased risk of AD. Advanced glycation end products (AGEs) are formed as secondary production from food processing. AGEs can help to induce oxidative stress and cause inflammation. These processes can modify the body’s protein and cell surface receptors. Malnutrition was also observed as increasing the chance of developing AD. Many patients with AD also suffer from malnutrition by having trouble eating and swallowing. This is because as one progresses through the late stages of AD, they begin to lose their motor functions affecting basic autonomic functions, such as chewing and swallowing. The loss of autonomic function will result in patients developing other health complications in the late stages of AD such as pneumonia [7]. 

Infection

Infections in the central nervous system can cause neurofibrillary tangles and amyloid beta plaques to form – which are the main characteristics of AD. There have also been several infections associated with AD such as HSV-1, Chronic bacterial infections, chlamydia pneumoniae. HSV-1, also known as Herpes Simplex Virus, is a virus that causes contagious sores that appear most often around the mouth or genital area. This virus was correlated with AD because the DNA of HSV-1 positive patients also had ApoE allele carriers – which constituted a higher risk of developing AD. HSV-1 can also increase the deposits of amyloid beta and activate the inflammatory response, which can damage neurons. Chronic bacterial infections, such as syphilitic dementia, were also correlated with AD. Syphilitic dementia can produce lesions in the brain by accumulating itself in the cerebral cortex. Chlamydia pneumoniae bacterium was also correlated with AD because it can activate astrocytes and cytotoxic microglia which contributes to calcium dysregulation. This results in apoptosis and can decrease cognitive function – increasing the risk of AD [7, 15].

Medical Comorbidities of AD

The current research around AD has led us to identify some medical comorbidities that may be related to the onset and pathology of AD. Understanding the relationships between these factors can better help scientists understand the disease and possibly find a cure. 

Obesity

Many studies have associated the metabolic changes that result from obesity to the development of AD. For example, obesity modifies cholesterol esterification and trafficking – both of which are associated with amyloid beta production. Higher free cholesterol levels in the neuronal membrane have also been shown to exert harmful effects in the processing of the neurons in the brain. [15]

Diabetes

Hyperglycemia and Hyperinsulinemia have been associated with AD along with the precursors of diabetes. Modifications in insulin have also been found to increase amyloid beta and reduce the degradation of tau. Modification in insulin comes from brain inflammation which increases microglia and decreases plasticity and neurogenesis. Microglia can block insulin signaling affecting the insult receptor substrate 1. Under normal conditions in the brain, insulin is a crucial hormone that helps to regulate fat and glucose levels, which play important homeostatic and neuroprotective roles such as, behavior, cognition and emotion. [7] 

Cancer

Cancer is a disease that is characterized by an uncontrolled division of abnormal cells in parts of the body. There has been an observed increase in the inverse relationship between cancer and AD. For example, P53 is a protein that is produced by a tumor-suppressor gene. Mutations in the P53 gene may cause cancer cells to grow and spread throughout the body.  It also has an inverse relationship in AD and cancer. For example, P53 is upregulated in AD and is downregulated in cancer. P53 also causes apoptosis and is downregulated in tumors to promote survival, where in AD it causes neuronal death [1].

There has also been an observed inverse relationship with cAMP – a molecule that is important in regulation of metabolism. For example, deregulation of cAMP is involved in tumor progression in cancer. But high amounts of cAMP contribute to an enhanced survival signal for neurons. TGF beta has also demonstrated an inverse relationship in AD and cancer. TGF beta is a multifunctional cytokine that plays an important role in wound regulation and immunoregulation. TGF beta is increased in AD and decreased in cancer to tumorigenesis in cancer [1].

Breast cancer is associated with mild cognitive impairment and changes in aging. Breast cancer was also associated with lower white matter organization and connectivity – which could increase the risk of developing AD later on. This could be linked to the Estrogen receptor gene, a gene also contributing to an increased susceptibility of AD. For example, the Estrogen Receptor is expressed in about 70% of breast cancer cases and plays an important role in the progression of tumors [3].

Stress/Depression

It is estimated that up to 40% of people living with AD also suffered from significant depression [2]. Depression can lead to cognitive decline and shares many symptoms with AD. For example, both common symptoms between depression and AD include impaired concentration, social withdrawal, loss of interest in hobbies and sleeping too much or too little. Stress is also involved in the development of many diseases by exerting a significant effect on the immune system and the Hypothalamic-Pituitary Adrenal (HPA) axis.  Excessive levels of stress get activated through the HPA axis, which regulates corticosteroid levels. Chronic stress has been identified with an increase in tau hyperphosphorylation and elevated amyloid beta in the CSF. Several studies have also correlated depression and late-life anxiety with the incidence of dementia [17].

Discussion

Diagnosis

Diagnosing AD has improved through the last couple of decades due to better technology and developing better biomarkers. For example, we can now use positron emission tomography (PET) scans to see amyloid beta plaques and neurofibrillary tangles in the brain. We can also do a spinal tap to measure cerebral spinal fluid to see the proteins in the brain. However, these procedures are invasive and costly [14]. Luckily, there have been advances in blood tests that allow us to see if someone has amyloid beta and tau in the brain. For example, a new blood testing technique, called Simoa, can measure the concentration of ptau181 in blood plasma. Through the analysis of ptau181 in plasma levels, scientists are better able to distinguish healthy patients from patients with AD [35]. These clinical tests are conducted if a patient is experiencing memory loss beyond aging, visual/spatial difficulties, problems finishing tasks, difficulty concentrating/problem solving, etc… [21]

Alzheimer’s Disease Continuum

Alzheimer’s disease follows three broad phases. This includes preclinical AD, mild cognitive impairment due to AD and dementia due to AD. The dementia phase is further broken down into mild, moderate and severe cases. The 1st phase (preclinical) phase includes the biomarkers (amyloid beta and neurofibrillary tangles) found with AD but no symptoms have developed. Amyloid beta plaques and neurofibrillary tangles can be found as early as 20 years before someone is diagnosed with AD. The mild cognitive impairment due to AD includes mild symptoms such as subtle problems with thinking and memory. These symptoms do not interfere with daily life [21].

Dementia due to AD is classified as symptoms interfering with everyday activities. The mild, moderate and severe classifications are characterized by how much symptoms interfere with everyday activities. For example, severe cases are where symptoms are interfering with most everyday activities; whereas, the mild cases are characterized by symptoms interfering with some everyday activities. In the late stages of AD (moderate and severe cases) patients may lose some autonomic function as the brain deteriorates. Loss in autonomic function contributes to patients acquiring further health complications such as infection or aspiration pneumonia [21].

Treatment

AD is irreversible and there are no symptomatic drugs that effectively treat the disease. However, there are things that may deter the onset of the disease. For example, exercise can increase cognitive function and deter the onset of Alzheimer’s [13]. Exercise can also increase the gray and white matter of the brain and can increase motor function. These processes help to go against the processes of aging [5]. Maintaining a high level of cognitive reserve (defined as the brain’s resistance to damage), may also help to deter the onset of the disease. For example, learning new things helps to create new synapses in the brain and build one’s cognitive reserve. When there are more synapses and connections between ideas, it decreases the chance of developing the AD. An example of this idea is by the Nun study.[25] The Nun study focused on a group of 678 Roman Catholic sisters. Those that participated were active in different cognitive tests and allowed researchers to analyze their daily lives. The participants also donated their brains when they died. When researchers were looking at the postmortem brains with no symptoms of Alzheimer’s, they found that some of the brains did have amyloid beta plaques and neurofibrillary tangles. Researchers suspect that the reason participants didn’t show any symptoms of AD, despite having the pathologies of AD, was because of a higher cognitive reserve. 

Conclusion 

AD is a multifactorial disease. Amyloid beta plaques and tau tangles are the main culprits for the pathogenesis of the disease; however, there are many other factors that can exacerbate or trigger the disease [15]. These can include genetic, environmental or medical factors. Alzheimer’s disease is also hard to diagnose as it is similar to many other conditions such as depression. Clinical diagnostic procedures are costly and evasive and don’t necessarily give a confirmed diagnosis [21].

More research still needs to be conducted. For example, amyloid beta plaques and neurofibrillary tangles can be found in the brain as early as 20 years before the onset of symptoms; however, as demonstrated by the Nun study individuals could still have amyloid beta plaques and neurofibrillary tangles in the brain. Knowing this could help guide researchers into studying the exact tipping point of the disease. For example, patients with amyloid beta plaques and neurofibrillary tangles may not show symptoms until they reach a certain threshold where AD pathology then develops. This may be a result of a higher cognitive reserve, exercise, or avoidance of the environmental factors that could worsen the disease. Patients with AD may have passed the threshold that allowed AD pathology to progress to the point of irreversibility. 

Understanding current relationships between AD and other factors may also help guide research into finding a cure. For example, understanding why there is an inverse relationship between AD and cancer may help researchers better understand AD pathology. The link between estrogen receptors and breast cancer contributing to AD pathology may also explain why there is a higher percentage of women with AD. However, until we overcome the pathology of AD, the best way to treat this disease is through prevention. Individuals should start to maintain and build their cognitive reserves and exercise daily. Screening prone individuals for biomarkers before they start showing symptoms may also be an effective way to inhibit the disease from passing the theoretical threshold of AD progression. 

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