Author: Mohammed Miqdad Husain
Mentor: Dr. Rosalyn D. Abbott, Carnegie Mellon University
Aging causes many changes in brain structure and is a risk factor for numerous diseases. Dementia is one such age-related disease that affects about one-third of all elderly people over the age of 85, according to the National Institute of Health1. Scientifically, the disease is a blanket term for a group of symptoms and is triggered by neurodegeneration, a state where neuronal cells in the brain or the peripheral nervous system die or lose function over time. Although, there are many different diseases that can lead to dementia, Alzheimer’s Disease (AD) remains the most prevalent cause. AD is a progressive disorder wherein atrophy of brain cells results in the death of neurons and degeneration of synapses in the hippocampus region, the part of the brain responsible for learning, memory, and spatial awareness2. Associations between the hippocampus and the cerebral cortex are vital for logical understanding, judgement, and spatial orientation. Hence, hippocampal neurogenesis is often marked by a decline in cognitive function and memory loss, becoming increasingly debilitating as it advances.
This devastating disease presents a significant global health challenge, particularly as the population continues to age, leading to a higher number of individuals at risk. Statistics produced by the Centre of Disease Control and Prevention (CDC) suggest that the prevalence of AD is expected to rise dramatically in the coming decades. There were 5.8 million Americans living with the diseases, with projections estimating that by 2060, the number could triple to over 14 million.
As the disease progresses, more severe symptoms emerge, such as confusion, disorientation, mood swings, and difficulty with language and problem solving. In the advanced stages of AD, patients become entirely dependent on their caregivers, often requiring round-the-clock support. In 2019, caregivers provided an estimated 18.5 billion hours of care3. AD not only affects the patients but also their families and caregivers. Behavioral changes and motor difficulties eventually follow in patients, resulting in substantial burden on caregivers. Caregivers and families of patients with AD are at a greater risk of anxiety and depression, therefore.
The precise causes of the disease remains unclear, though advancements in technology have driven medical researchers to conclude that there is no single cause but several factors that affect each patient differently. The most likely contributor to the gradual erosion of cognitive brain function is the agglutination of amyloid plaques in the extracellular space in the neuronal cavity. Other pathological factors include to the accumulation of the tau protein, which disrupts the normal functioning of neurons, and neuroinflammation, triggered by the activation of microglial cells.
This paper aims to provide an overview of the risk factors, symptoms, and pathological hallmarks pertaining to AD: the various cell types, neurons, and glial cells involved in the neurodegenerative disorder. The paper will also discuss the development of novel therapies that consider the intricate play between genetics, lifestyle factors, and environmental influences.
Although age is the most paramount cause of AD, it is important to remember that this disorder is not a normal part of aging. The probability of developing AD doubles every five years after the age of 65 and the risk reaches nearly a third after the age of 85. However, it is not only the elderly who develop AD. According to the National Health Services (NHS)4, 5% of all affected by the disease are under 65. This phenomenon is known as early-onset Alzheimer’s Disease.
There are two types of genes, risk and deterministic, that influence whether an individual obtains the disease. Risk genes increase chances of a person developing a disease, but having the genes does not make it certain that they will acquire it. Scientists have identified the APOE- e45 gene to have the most significant impact on risk, with approximately 40-65% people with AD having the gene.
However, having deterministic genes for AD means an individual inheriting the gene will directly have the disease. Although rare, scientists have found that AD caused by these hereditary deterministic genes account for only 1% of all the diagnosed cases.
2.3 Down’s Syndrome
A traditional baby is born with 46 chromosomes. However, babies born with Down Syndrome6 have an extra copy of chromosome 21, which can accelerate the possibility of an AD diagnosis. Chromosome 21 carries the gene that codes for the amyloid protein that is responsible for some of the brain changes associated with AD. Having this extra gene along with other conditions like cardiovascular abnormalities can also increase the risk.
2.4 Cardiovascular Disease
A study conducted by Neurology suggests that hypertension, in other terms high blood pressure, can cause cerebral thrombosis7. Researchers found that patients in the study had more tangles of protein, disrupting the normal functioning of neurons and brain cells. This augments the risk of cognitive impairment due to limited performance in the temporal lobe, the region in the brain responsible for memory and recognition.
The early stages of AD involve subtle memory lapses and difficulty in concentrating, which often go unnoticed or are mistaken for normal age-related cognitive decline. AD is a progressive disorder, meaning the disease gets worse with time. As the disease progresses, more severe symptoms emerge, such as confusion, disorientation, mood swings, and difficulty with language and problem solving. In the advanced stages of Alzheimer’s, patients can become entirely dependent on others for their care, often requiring round-the-clock support.
3.1 Brain Changes of Alzheimer’s Disease
A healthy brain is made up of millions of neurons with long branching extensions at the ends called dendrites. These structures allow neurons to establish connections with each other. Between two adjacent neurons is an empty space called synapse, where chemicals called neurotransmitters released by one neuron are taken up by the other neuron, allowing signals to be quickly transmitted through the brain. It is because of these signals that the brain can interpret environmental stimuli to process memory, refine motor skills, and become spatially aware.
However, in brains diagnosed with AD, excess accumulation of beta-amyloid plaques in the extracellular space of neurons, and the accumulation of tau protein tangles in the intracellular space of neurons interferes with a neuron’s capacity to transmit information. This abnormal activity leads to several changes in the structure of the brain that is linked with AD. The accumulation of both the tau protein tangles and β-amyloid damages the neurons, leading to neurodegeneration. However, both hallmarks play a different role in the development of the disease, which will be discussed in subsequent sections.
3.1.1 Beta-Amyloid Plaques
Plaques in the AD diagnosed brains are microscopic lesions with a core of β-amyloid surrounded by enlarged axonal endings. The β-amyloid chains are a product of the proteolytic degradation of a transmembrane protein called amyloid precursor protein (APP) by a combination of the action of α-secretase, β-secretase and γ-secretase enzymes. Non-toxic peptide chains of the β-amyloid protein is cleaved by the action of either the α-secretase or the β-secretase enzymes. However, a cascade of disintegration by sequential action of the β-secretase and γ-secretase enzymes result in the production of a 42 amino acid peptide, β-amyloid 42, which supports the formation of aggregated fibrillary amyloid protein8. A rise in the levels of β-amyloid 42 leads to deposition of amyloid, causing neuronal toxicity.
Calcium ion channels are located at the axonal bouton of neurons and are permeable to calcium ions. These ions are integral to the exocytosis of synaptic vesicles containing neurotransmitters, thus initiating the process of synaptic transmission. However, when calcium ion channels are blocked, synaptic transmission is inhibited. In Alzheimer’s, soluble β-amyloid 42 oligomers assimilate in the cellular membrane of neurons and build amyloid channels that are permeable to calcium ions9. This disrupts the homeostasis of calcium ions in the axonal bouton, severely affecting synaptic transmission, which eventually leads to the degeneration of neurons.
3.2 Tau Proteins
In addition to amyloid plaques, another pathological hallmark of AD is the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein. These tangles, like amyloid plaques, also disrupt the normal functioning of neurons, leading to their degeneration and eventual death. Tau proteins exist in a microtubular form and are responsible for stabilizing the internal structure of a neuron. Under normal conditions, it acts as a channel protein that enables nutrients and other vital substances to enter and exit the neuron. However, some pathologies can cause the tau proteins to phosphorylate, inducing neuronal toxicities10.
Modifications to the traditional structure of tau proteins are caused by chemical activities in the brain, which change the three-dimensional structure of the proteins11. The microtubular form breaks and reassembles as neurofibrillary tangles that accumulate in the intracellular matrix of the neurons. This altered form of tau is not effective in removing waste products produced inside the neurons and affect cellular function. Scientists at National Institute of Health have found that in AD, abnormal chemical activities in the brain that cause this alteration are due to an imbalance in the levels of the β-amyloid proteins12.
Neuroinflammation has played a pivotal role in the pathogenesis of AD. This inflammation exacerbates the accumulation of amyloid plaques and tau tangles and contributes to neuronal death. Inflammation is one of the body’s defense mechanisms to combat infections. However, in AD, the equilibrium of pro-inflammatory and anti-inflammatory signaling is interrupted, activating microglial cells13.
Microglia are a type of immune cells within the central nervous system (CNS). At the resting state, microglia utilize cell signaling mechanisms, using receptors for neurotransmitters and cytokines, to detect foreign bodies in the surrounding neuronal environment. Upon recognition of threat to the CNS, a morphological change occurs transitioning the microglial cells into the activated state. This results in migration and enlargement of the cell soma.
With AD, however, the transition to the activated state can be triggered by the presence of β- amyloid in the neuronal environment. The activated microglia migrate to the site of β-amyloid and engulf the polypeptide through a process called phagocytosis. After a prolonged period of exposure to β-amyloid, the cell soma abnormally enlarges and the microglia are no longer able to process and phagocytose the protein, exacerbating the pathology of AD.
Data suggests that the ability of microglia to produce pro-inflammatory cytokines is unaffected14. These cytokines are responsible for the up regulation of inflammatory reactions as a defense mechanism to get rid of infections in the body. Therefore, the ongoing production of cytokines worsens inflammation in the brain and contributes to neurodegeneration, causing more microglia to become activated in a negative feedback cycle.
4. Treatment Strategies
4.1 Toll-like Receptors (TLRs)
Pattern recognition receptors are utilized by the immune system to detect pathogens and endogenous molecules generated in response to injury. For example, TLRs are expressed on microglial cells and trigger transcriptional activation of pro-inflammatory genes when stimulated. Modulation of TLR signaling and other immune pathways may provide potential therapeutic targets for Alzheimer’s Disease.
The use of antibodies targeting specific inflammatory mediators or the development of small molecules that modulate immune cell function could be promising strategies for treating Alzheimer’s Disease.
4.2 Anti-Inflammatory Drugs
At present, the Food and Drug Administration (FDA) has approved only six non-steroidal anti- inflammatory drugs (NSAIDs), namely Rivastigmine, Galantamine, Donepezil, Memantine, Memantine combined with Donepezil, and Tacrine15. These drugs only provide symptomatic relief and work by inhibiting the activity of the cyclo-oxygenase (COX) enzyme, which is responsible for the inflammation widespread in AD brains. NSAIDs work by perpetuating the homeostasis of calcium ions, preventing the degeneration of neurons.
Certain other NSAIDs like Sulindac, Ketorolac, Ibuprofen etc. also inhibit the accumulation of β-amyloid, which intercepts the formation of neurofibrillary tangles and the inflammatory response that follows. However, more extensive and well-designed studies are required to establish the potential benefits of anti-inflammatory drugs for AD.
4.3 Disease-Modifying Techniques
Researchers are investigating drugs that target the underlying pathophysiology of Alzheimer’s Disease, such as the production of β-amyloid and the aggregation of tau proteins. These disease- modifying therapies aim to slow down or halt the progression of the disease, rather than just alleviate the symptoms. Recent clinical trials have shown promise in some of these therapies, but further research is needed to establish their safety and efficacy.
4.4 Stem Cell Therapy
Research into stem cell therapy offers promising avenues for treating Alzheimer’s Disease16. The potential of stem cells to differentiate into various cell types, including neurons and glial cells, could help replace degenerated neurons and promote their regeneration.
Pathogenesis of AD includes many different processes, including apoptosis and inflammation. Research on potential treatments conducted using animal models suggest that β-amyloid peptides cause apoptosis of neurons17. Studies have proposed that transplanted stem cells could have the capacity to lower the levels of β-amyloid in the hippocampus by inducing cells to produce enzymes that break down the β-amyloid plaques in the neuronal environment.
Furthermore, stem cells can also secrete growth factors and modulate the immune response, potentially alleviating inflammation and promoting repair in an Alzheimer’s disease-affected brain.
4.5 Lifestyle Interventions
While pharmacological therapies are crucial in the management of Alzheimer’s Disease, lifestyle interventions play a significant role in preventing and managing the disease. These interventions include a healthy diet, regular physical activity, cognitive stimulation, and social engagement. Epidemiological evidence suggests that adopting a healthy lifestyle may reduce the risk of developing AD and improve cognitive function in individuals already diagnosed with the disease.
However, further research is needed to better understand the mechanisms underlying the benefits of lifestyle interventions and to develop tailored strategies for individuals at different stages of Alzheimer’s Disease.
Alzheimer’s is a complex neurodegenerative disorder with multiple contributing factors, including amyloid plaques, tau protein accumulation, and neuroinflammation. As our understanding of the disease improves, researchers are exploring various treatment options, such as immune system modulation, anti-inflammatory drugs, disease-modifying therapies, stem cell therapy, and lifestyle interventions. Continued research efforts are necessary to develop effective therapies and ultimately alleviate the burden of AD on patients and their families.
The development of novel therapies requires a multidisciplinary approach that considers the intricate play between genetics, lifestyle factors, and environmental influences. Moreover, personalized medicine approaches that consider an individual’s unique genetic makeup, risk factors, and disease progression may lead to better treatment outcomes. It is essential to support research initiatives, facilitate collaboration among scientists, and foster public awareness to overcome the challenges posed by the disease and improve the lives of millions of people affected by this devastating disorder.
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