Genetic Causes, Biological Effects, and Treatment of Alzheimer’s Disease
The prevalence of dementia grows increasingly alarming and there has been enormous effort, on the part of health care providers, to understand and treat the condition. Dementia is an umbrella term for a decline of mental ability that is severe enough to interfere with daily life. The most common type of dementia is Alzheimer’s disease, responsible for approximately 70% of all dementia cases (Castellani). It is also one of the leading causes of death in the United States (“Alzheimer’s Disease”). Currently, there is no cure for Alzheimer’s and treatments are focused on the management of its symptoms, despite the progress in understanding the disease. While medications and common preventative measures, such as physical activity and nutritious diets, are regarded to be effective in maintaining overall health as well as controlling symptoms, unconventional treatments, like gene-editing and neuroprosthetics, should also be taken into consideration as possible treatments for Alzheimer’s disease. Alzheimer’s disease is a progressive deterioration of cognitive and physical function marked by the accumulation of amyloid plaques, occurrence of neurofibrillary tangles, chronic inflammation, and the degeneration of brain tissue.
In a healthy brain, the breakdown of amyloid precursor protein (APP) forms amyloid-? peptides. Amyloid-? peptides naturally collects between neurons. When there are abnormally high levels of these peptides, including amyloid-? 42 which is considered to be especially toxic, clumps of the protein are created (“What Happens to the Brain”). Amyloid plaques are formed once the clumps harden in the synapses between neurons, thus disrupting cell signals traveling from one neuron to the next (“Brain Tour”). Chronic inflammation also occurs in the brain of an individual with Alzheimer’s disease, which may be caused by the inadequate removal of waste, debris, and protein collections, including amyloid-? plaques, from the synapses (“What Happens to the Brain”). A gene that contains a triggering receptor expressed on myeloid cells 2, otherwise known as TREM2, stimulates microglia to clear amyloid-? plaques from the brain by way of phagocytosis, engulfing materials (Condello 2). This helps fight against inflammation in the brain. Nevertheless, when mutations of this gene causes a malfunction in phagocytosis, plaques are found to build up in the synapses of the brain due to the failure of microglia and astrocytes to perform their function of clearing the debris. Moreover, activation of microglia is associated with the release of chemicals, such as cytokines and free radicals, which further exacerbates inflammation resulting from plaque build-up as well as damage the neurons they are supposed to protect (Condello 2).
Unlike amyloid protein that accumulates externally, a protein called tau collects within neurons. Normally, tau proteins stabilize microtubules, which help transport nutrients and other substances through the interior of a nerve cell. However, abnormal chemical changes due to Alzheimer’s disease cause tau to detach from microtubules and bind to other tau molecules (“The Progression of Alzheimer’s”). In doing so, the tau molecules form threads that eventually join to form neurofibrillary tangles inside neurons and blocks the neuron’s transport system, harming the synaptic communication that occurs between neurons (“Brain Tour”). In fact, abnormal tau molecules tend to accumulate in specific regions of the brain, such as the entorhinal cortex and hippocampus, that are involved in memory (“What Happens to the Brain”). This suggests a connection between the occurrence of neurofibrillary tangles and the memory loss that is symptomatic of Alzheimer’s disease.
Not only is the brain affected by Alzheimer’s, but vascular problems are also seen in patients with dementia. Amyloid-? deposits can collect in arteries, which would affect blood vessels if the deposits harden into plaques and lead to the hardening of the arteries (atherosclerosis) and mini-strokes. Furthermore, vascular problems in relation to Alzheimer’s include reduced blood flow and oxygen to the brain, as well as a breakdown of the blood-brain barrier, which protects the brain from harmful agents while allowing in necessary factors (“What Happens to the Brain”). A faulty blood-brain barrier prevents glucose and other substances from reaching the brain as well as toxic amyloid-? and tau proteins from being cleared away, which results in inflammation.
In Alzheimer’s disease, as neurons become injured and die throughout the brain due to plaque and tangles disrupting nerve cell communication, connections between networks of neurons may break down. Eventually, the resulting brain atrophy becomes widespread throughout the brain and there is a significant loss of brain volume due to cortical and hippocampal shrinkage as well as enlargement of ventricles, cavities in the brain where cerebrospinal fluid is created (“The Progression of Alzheimer’s”). This leads to the cognitive impairment seen in those diagnosed with Alzheimer’s.
Regions of the brain that are involved in memory, such as the entorhinal cortex and hippocampus, are affected first by Alzheimer’s. The hippocampus is a brain structure that plays a critical role for learning and memory. When damaged, the hippocampus affects the short-term memory of an individual and leads to the inability to remember recent events, such as a conversation or where they put their car keys (Wighton). The hippocampus is also responsible for orientation and damage may result from an individual becoming lost during a familiar excursion, such as driving home from work. Therefore, memory problems are typically one of the first signs of cognitive impairment. Following the memory areas of the brain, the cerebral cortex that is responsible for language, reasoning, and behavior becomes affected as well. Meanwhile, the cortex is responsible for long-term memory, reasoning, thinking, and mood (Wighton). Deterioration of the cortex may also cause impaired language and judgement along with emotional outbursts to occur (“The Progression of Alzheimer’s”). Consequently, the National Institute of Aging stated that “the decline in non-memory aspects of cognition, such as word-finding, vision and spatial issues, and impaired reasoning or judgment,” signals the early stages of Alzheimer’s disease (“What Are The Signs”). Hence, it is important to recognize the signs and symptoms of Alzheimer’s to provide individuals with proper treatment and care during the beginning stages of the disease.
There are several risk factors for Alzheimer’s disease, yet the most important known risk factor of the disease is increasing age. In fact, according to the CDC, the number of people with the disease doubles every five years beyond the age of sixty-five (“Alzheimer’s Disease”). Age-related changes including brain atrophy, inflammation, and the accumulation of cellular waste products, such as free radicals, may contribute to damage that is resulted from Alzheimer’s disease (“What Causes Alzheimer’s”). Considering its prevalence in the elderly population, the most common type of Alzheimer’s disease is late-onset Alzheimer’s Disease, when signs of the disease appear in an individual during their mid-60s or later. There is a combination of genetic, environmental, and lifestyle factors that affects the risk of developing the disease. However, a genetic risk factor has been found to increase an individual’s risk of acquiring Alzheimer’s disease involving a gene called apolipoprotein E (APOE) on chromosome 19 (“What Causes Alzheimer’s”). APOE has three different alleles: APOE ?2, APOE ?3, APOE ?4. APOE ?2 is considered to be relatively rare and considered to provide protection against the disease since Alzheimer’s is seen to develop much later in life than it would in someone with APOE ?4 (“What Causes Alzheimer’s”). APOE ?4 increases the risk for Alzheimer’s disease. It is also associated with an earlier age of onset. Although, it does not mean the individual will definitely develop the disease. The more APOE ?4 alleles one has elevates the risk for that person to develop Alzheimer’s. APOE ?3 is the most common allele of the three and is plays a neutral role concerning Alzheimer’s disease.
In spite of the misconception that Alzheimer’s disease merely occurs in the elderly population, about five percent of all Alzheimer’s patients are diagnosed with early-onset familial Alzheimer’s disease, which occur in those ages thirty to fifty years old (“What Causes Alzheimer’s”). This type of Alzheimer’s is usually caused by inherited changes in one of three deterministic genes passed down from parent to child, who then has a fifty percent chance of inheriting that mutation and developing the disease. Therefore, family history plays a role in the development of early-onset familial Alzheimer’s disease. Single gene mutations on chromosomes 21, 14, and 1 causes abnormal proteins to be formed and plays a role in the breakdown of APP, which is part of a process that generates amyloid plaques (Castellani). A mutation in Chromosome 21 results in the formation of abnormal APP. A Chromosome 14 mutation causes abnormal presenilin 1 is made. Presenilin 1 carries out the function of cleaving other proteins into smaller peptides, therefore it has a role in the generation of amyloid-? peptides from APP (“PSEN1 Gene”). The production of abnormal presenilin 1 leads to overproduction of a longer, toxic version of amyloid-? peptide, which could clump together and form amyloid plaques in the brain. In fact, mutations in the Presenilin 1 gene are the most common cause of early-onset Alzheimer’s and accounts for up to seventy percent of cases (“PSEN1 Gene”). Furthermore, a mutation in Chromosome 1 leads to abnormal presenilin 2, which also breaks down APP.
Due to the genetic risk factor that these mutations present, there are hopes to using gene-editing as a future treatment for Alzheimer’s. Early findings, by scientists from the Imperial College of London, suggests a gene called peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-?) may prevent the formation amyloid-? peptides in cells (Wighton). The team of scientists used amyloid precursor protein (APP23) transgenic mice as a model for Alzheimer’s patients during the preclinical stage of the disease, when amyloid plaques are not yet developed. A lentivirus vector, a modified virus commonly applied in gene therapy, was used to contain and deliver PGC1-? due to its ability to infect cells (Wighton). The lentivirus along with the PGC1-? gene is injected directly into the brain. Four months later, the team discovered that APP23 mice “showed improved spatial and recognition memory concomitant with a significant reduction in A? deposition”, which means that the mice who received the gene had fewer amyloid plaques, compared to the untreated mice (Katsouri et al.). As a result, the treated mice performed as well as healthy mice in memory tasks, such as exploring a new object for longer than a familiar one. The team also found that the mice who received the gene treatment experienced a reduction in the number of glial cells, thus decreasing cell damage caused by the release of inflammatory substances, and no loss of brain cells in the hippocampus (Wighton). It has been suggested injections of the gene would be most beneficial in the early stages of the disease, when the first symptoms appear.
Another unconventional treatment for Alzheimer’s disease that may be possible in the future is neuroprosthetics, more specifically hippocampal prostheses. Dr. Eun Young Song describes hippocampal prostheses as “implantable microelectrode arrays placed on the hippocampus of the brain to enhance cognition” (Song). Ted Berger, Dong Song, Robert Hampson, and their colleagues have constructed a hippocampal prosthesis that identify patterns of brain activity tied to particular experiences and then, when called upon, impose those patterns on the brain via electrical stimulation (Frank). This system, in the form of a small neural chip, was inserted into the hippocampus of subjects, which are often rats. The chip monitors the electrical impulses of individual neurons as a rat is trained to perform a task, and the signals generated are then compiled into a pattern and transformed into an algorithm. The researchers found that the subjects were able to “remember” how to carry out the task they were taught if they were stimulated by the correct impulse patterns despite having had the ability to form their own memories turned off (Frank). This demonstrates the potential of neuroprosthetics to be a treatment for Alzheimer’s disease. However, it has been acknowledged by Dr. Laura Cabrera that “although brain stimulation techniques offer considerable benefits to society, they also raise a number of ethical concerns” (Song).
Even though gene-editing and neuroprosthetics have potential, medication and management strategies are used as the current treatments in managing symptoms of Alzheimer’s. Prescribed medication are seen to be effective for people in the early or middle stages of Alzheimer’s. Typically, patients are started with low drug doses and the dosage is gradually increased based on how well a patient tolerates the drug. For mild to moderate Alzheimer’s, cholinesterase inhibitors are given to treat symptoms related to memory, thinking, language, judgment and other thought processes (“FDA-Approved Treatment”). Alzheimer’s disease tends to damage or destroy cells that produce and use acetylcholine, which is essential in processing memory and learning, and, thereby, reducing the amount of the neurotransmitter available to carry messages, decreasing the focus and attention of a patient (“FDA-Approved Treatment”). A cholinesterase inhibitor blocks the activity of acetylcholinesterase, which slows the breakdown of acetylcholine. By doing so, acetylcholine levels are maintained and the drug may also aid in compensating for the loss of functioning neurons. Razadyne® (galantamine), Exelon® (rivastigmine), and Aricept® (donepezil) are examples of common cholinesterase inhibitors (“How is Alzheimer’s”). Unlike the other inhibitors, Aricept® is approved for all stages. It has been recognized that those with Alzheimer’s disease may respond to one drug better than another. While cholinerase inhibitors are generally well tolerated, common side effects include nausea, vomiting, loss of appetite and increased frequency of bowel movements (“How is Alzheimer’s”).
For moderate to severe Alzheimer’s, N-methyl D-aspartate (NMDA) antagonists are given due to Alzheimer’s causing the body to have excess glutamate (“How is Alzheimer’s”). Usually, NMDA allows glutamate to enter cells and is critical for synaptic plasticity and survival of neurons. However, when there is a surplus of glutamate, NMDA receptors become overstimulated. The receptors, then, allow too much calcium into the nerve cells, leading to the disruption and death of cells. Namenda® (memantine) is an NMDA antagonist drug that protects cells against excess glutamate by partially blocking NMDA receptors in order to regulate glutamate activation (“FDA-Approved Treatment”). This medication decreases symptoms and could allow some individuals to maintain certain daily functions a little longer than they would have without the medication by improving memory, attention, reason, language and the ability to perform simple tasks (“FDA-Approved Treatment”). Common side effects of Namenda® include dizziness, headache, diarrhea, constipation, and confusion.
Cholinesterase inhibitors and NMDA antagonists can also be prescribed in combination. Namzaric® is a combination of Namenda® and Aricept® (“How is Alzheimer’s”). This medication blocks the toxic effects associated with excess glutamate as well as prevent the breakdown of acetylcholine in the brain. Namzaric causes side effects such as headache, nausea, vomiting, diarrhea, dizziness, and anorexia.
Although there is no current cure to stop the disease, preventative measures are recommended to slow the development of Alzheimer’s disease. A healthy diet, physical activity, community involvement, and mental stimulation have all been associated with helping people stay fit as they age. On average, those with Alzheimer’s live for eight to ten years after diagnosis, but can last for as long as twenty years (“The Progression of Alzheimer’s”). During that time, an individual with the disease suffers through a decline of memory and cognition, which tends to result in increased anxiety and aggression within that individual. When a person gets diagnosed with Alzheimer’s, it not only affects them, but everyone around them such as family, friends, and caregivers. While those in science continue their efforts to find a cure, it is for these individuals and future generations affected by Alzheimer’s that one must understand the causes and effects of the disease as well as treatments, such as gene-editing, hippocampal prostheses, and prescribed medications.
Genetic Causes, Biological Effects, and Treatment of Alzheimer’s Disease