As a result of the rapidly advancing medical science, the life expectancy of many populations around the world has seen a considerable increase in recent decades. That luxury, however, is not without costs. One of the many implications of this situation is the increased incidence of degenerative diseases that develop with advanced age.
Alzheimer’s is the most common neurodegenerative disease in the world. An estimated 5.8 million people who are 65 years or older live with Alzheimer’s disease in the US in 2020, and the number is growing. Fast. This exponentially increases the possibility of you having to deal with it either as a patient or as a caretaker.
Table of Contents
What is Alzheimer’s Disease?
Alzheimer’s disease (AD), as we mentioned earlier, is a neurodegenerative disease. With age, the neurons in your brain die or lose functionality. Even though this is a normal process in aging, excessive neuronal death is thought to be the cause of AD. But, the exact underlying mechanisms are not fully understood yet. Even though aging is a significant risk factor for AD, it is worth noting that it is not the only cause. Also, AD is not a part of the normal process of aging.
Patients with late-onset AD, the most common type of the disease, show symptoms usually after the mid-60s of age. Early-onset AD, where symptoms manifest between 30 to 65, is a very rare form of the disease. The most worrisome fact about this disease is that it cannot be reversed or halted. Therefore, while the search for a definitive treatment goes on, treatment modalities focus on increasing the quality of life for the patients diagnosed with AD.
Pathophysiology
Since the disease was first described by Dr Alois Alzheimer in 1906, scientists have relentlessly tried to understand the exact pathogenesis of AD. Although the exact mechanisms are yet to be unveiled, they have proposed several hypotheses based on current findings, and they direct the currently practiced mainstream treatment strategies.
Brains of the diseased patients show abnormal clumps (amyloid plaques/ senile plaques), tangled bundles of nerve fibers (neurofibrillary tangles), and loss of connections between the neurons on post mortem histology. These features are thought to be developed by two main mechanisms; extracellular deposition of beta amyloid and intracellular accumulation of tau protein, both of which are insoluble when present in the form of polymers.
Beta Amyloid Plaques
Beta amyloids are formed when a precursor molecule called amyloid precursor molecule is cleaved by the action of beta and gamma secretase enzymes. Defective clearance of resultant beta amyloid proteins cause them to be clumped as plaques extracellularly as soluble oligomers, and later, convert to insoluble polymers. Subsequently, they weaken communication and plasticity at the synaptic level. This might be the reason for the patients’ inability to form or retrieve memory.
Also, after reaching a threshold level, they are believed to activate the intracellular deposition of tau protein as well, about which we will be talking in a minute.
Abnormal Inflammatory Response
Neurons are not the only type of cell affected by Alzheimer’s disease. Microglia, the resident macrophages of the brain, try to help clear excess amyloid beta by phagocytosing them. But, they get activated in the process and release inflammatory cytokines that ultimately damage the brain tissue. They also attack and phagocytose synapses and remove them, leading to abnormal activity of the brain, leading to the inability to store and process information.
Tau Protein
In their normal forms, tau protein helps to stabilize the microtubules that help in transporting nutrients and other compounds along the length of healthy neurons. In AD, for some reason, they detach from these microtubules and adopt an abnormal shape by misfolding. Beta amyloid is thought to have a role in inducing misfolding of tau by activating kinase enzymes.
They aggregate and form insoluble deposits inside the neurons. Eventually, the unstabilized microtubules get destroyed, making the neuron unable to transport nutrients and other chemicals, further deranging the cellular function.
Researchers have also found that tau protein has the ability to travel into adjacent neurons via synapses, which might be a cause for the spread of pathology across the brain.
These mechanisms eventually lead to neuronal death leading to the shrinking of the brain. Hippocampus, which plays a vital role in forming memories, is one of the first areas to be affected by all these mechanisms. Then the degeneration spreads to the limbic system and subsequently to the prefrontal cortex. The clinical symptoms match the areas of degeneration along the course of the disease.
With neuronal death, the brain gets atrophied, leading to narrower gyri, wider sulci, and larger ventricular spaces.
Is Dementia the same thing as Alzheimer’s?
Dementia refers to progressive memory and thinking problems that affect your day-to-day activities. This is sort of an umbrella term that includes many different conditions like Alzheimer’s dementia, vascular dementia, Lewy body dementia, and frontotemporal dementia.
Although AD is the most common condition that leads to dementia, it is worth noting that these two terms do not refer to the same thing. Simply put, Alzheimer’s is a specific disease, and dementia is used to describe a condition caused by several diseases.
Symptoms
As this disease is a slowly progressing disease, symptoms in the early stages might not even be detected by the patients or even their closest members in the family. With the progression, however, the patients can experience short term memory loss, and later, loss of motor skills, which will make activities like eating difficult to perform without help. Also, their speech and language functions will be affected, along with personality and mood changes, making it harder to communicate.
In later stages, they can lose long term memory, making them unable to identify friends and family. Further down the track, they will get disoriented, which can cause them to wander off from home and get lost or to be bed-ridden. The ultimate cause of death for most patients, however, is infections like pneumonia. This is because as the disease affects more basic functions like respiration and heart rhythm, they become more vulnerable to infections.
The definitive diagnosis can only be made after visualizing characteristic plaques and neurofibrillary tangles on a brain biopsy after the death of a patient. Therefore, the clinical diagnosis is usually made by exclusion of other diseases.
Current Treatment Strategies
There is no known way to halt or reverse the progression of the disease yet. Therefore, medical treatment solely focuses on reducing the severity of symptoms. The two main categories of drugs used for this purpose are AChE inhibitors (acetylcholinesterase inhibitors) and NMDA receptor antagonists. These classes of drugs aim the neurotransmitters acetylcholine and glutamate, respectively.
Acetylcholinesterase Inhibitors
Acetylcholine (ACh) is a very important neurotransmitter in communication between neurons. In normal circumstances, the acetylcholinesterase (AChE) enzyme helps to prevent the build-up of ACh in the synaptic cleft. But in AD, communication between neurons is already impaired. Therefore, AChE inhibitors decrease the breakdown of ACh into acetyl and choline segments by AChE, resulting in slightly higher concentrations of ACh in the brain, causing a mild alleviation of symptoms.
Treatment with AChE inhibitors is indicated in patients with mild to moderate Alzheimer’s disease. 50% of these patients can be treated with considerable success for about 6 to 12 months with AChE inhibitors. Although it is usually well-tolerated, some mild adverse effects include nausea, vomiting, and loss of appetite.
N-Methyl-D-Aspartate Receptor Antagonists
N-methyl-D-aspartate (NMDA) receptor antagonists, on the other hand, target another neurotransmitter, glutamate. Memantine is the most commonly used drug in this category for Alzheimer’s. This medicine, however, is indicated only in patients with moderate to severe forms of the disease, whose memory, language, and reasoning skills are significantly impaired. Also, it is indicated only if potential benefits outweigh the risks.
Glutamate is an excitatory neurotransmitter that helps the learning and memory functions of the brain. However, when the levels are too high, it can give rise to the condition called “excitotoxicity,” where the brain cells can even die due to overstimulation. This is also a hypothesized mechanism of neuronal death in patients with Alzheimer’s.
NMDA receptor antagonists act by inhibiting the NMDA receptors (the type of receptor/channel that initiates ion influx when it binds with glutamate) that are located in the membrane of the receiving neuron. Memantine binds to NMDA receptors preventing them from binding with glutamate. This will reduce the excitation of neurons while lowering the rate of cell death, improving symptoms like memory and language impairments.
Memantine is sometimes used alongside AChE inhibitors, and their notable adverse effects include headache, dizziness, and confusion.
Non-Drug Interventions
Non-drug treatment modalities for AD have been thoroughly researched throughout the years due to the absence of disease modifying drug treatment options. These approaches, though they lack high quality research based evidence, are believed to improve patients’ cognitive functions and decrease their dependence. They also emphasize the need for loving and caring relationships with a supportive environment for patients.
Commonly practiced non-drug treatment options include cognitive therapy approaches like arithmetic exercises, the image recognition tests, and reality orientation by orientation aids; physical, social, and emotional stimulation activities like discussion groups and cooking together; emotion-oriented exercises like validation therapy and reminiscence therapy.
Research on these interventions, however, have resulted in mixed results. Also, they should always be overseen by an expert in the field as they may increase the patients’ confusion if done wrongly.
Another essential point to mention here is that the caregivers should have a comprehensive understanding of the disease itself and the importance of their relationship with the patient. They are recommended to receive formal training on the subject for better patient care.
Prevention
Preventing Alzheimer’s might be a way more effective approach for the disease than searching for a cure. But our incomplete understanding of the exact pathogenesis and the triggers of the condition is a barrier to it. However, considering the available knowledge and evidence, there are some expert recommendations. They include stopping smoking, reducing alcohol consumption, exercising, maintaining proper sleep hygiene, and most importantly, staying mentally and socially active.
There was a study called “ Nun study”, which started in 1986, which gave a lot of insight into developing preventing strategies. In this study, 678 nuns who were over the age of 75 when the study began were followed for around 20 years with medical examinations. All of their brains were donated for research after they died.
The histological examination of these brains left the scientists stunned. Despite the presence of numerous plaques, neurofibrillary tangles, and significant brain atrophy, which are features suggestive of obvious Alzheimer’s, some of these nuns did not manifest any cognitive or memory impairment till they died.
Based on these findings, the scientists’ speculation was that it was due to the higher level of cognitive reserve that the nuns possessed. This is just another way of saying that they had more functional synapses. This enables the brain to establish more connections between neurons (synapses).
A high level of cognitive reserve is seen in people with more years of formal education, a higher degree of literacy, and in people who engage in regular mentally stimulating activities like learning a new language, meeting new friends, and reading books. The more these activities integrate aspects like vision, hearing, and emotions, the better.
Potential leads for new treatment strategies
As we have mentioned repeatedly, the lack of definitive treatment is a huge drawback in the attempts of helping AD patients. The enormous sums of money dedicated to research have not yet resulted in any real treatment. However, many scientists are hopeful that with extensive research, a new convincing therapy might be just around the corner. We will discuss some of the most recent drugs and procedures in the making and their potential in helping the people in need.
Advancements in Diagnosing
In earlier days, the definitive diagnosis was only possible through autopsy. This is, for the most part, true in the current setting as well. However, with recent advancements in diagnostic technologies, a new method of identifying people who are on their way to AD, has been developed. This method uses a new biomarker identified by PET (positron emission tomography) scanning and is pending FDA approval.
Aducanumab
This is a biologic developed by Biogen. It targets to prevent toxic amyloid oligomer formation. Biogen halted their clinical trials after phase II came up with mixed results. Still, after a thorough analysis revealed that the participants who had the higher dose of the drug did have significant positive effects, they have decided to apply for approval from FDA.
ALZ-801
This drug, developed by Alzheon, targets the same target as aducanumab.ALZ-801 is an oral competitor to aducanumab, which is an IV antibody. Their plan is to start a two to three year-long phase III clinical trial next year.
GV-971
A biotech company based in Shanghai has an entirely different approach to the disease. Their drug targets the gut microbiome instead of targeting compounds in the brain. This is based on several studies on the matter at hand. The primary ingredient in their drug, which is an extract from seaweed, is said to “therapeutically harnesses the abnormal production of amino acids, infiltration of immune cells to the brain, and in turn neuroinflammation via remodeling the gut microbiota.” This drug is also on the verge of getting into phase III.
Research at MIT
Considering the huge disease burden of Alzheimer’s disease, it would be not surprising to learn that experts from various fields are trying to find a cure for it. A research team at MIT has been able to elicit a correlation between brainwaves and microglia activity. Their finding states that brainwaves of certain frequencies stimulate microglia and scavenger cells in the brain to consume toxic amyloid deposits. Further research is being done to confirm the feasibility of this therapeutic option.
Even though none of the studies have resulted in conclusive results, we are closer to a breakthrough than ever. Therefore, all of us can have our hopes high for a better future with less disease burden through prevention and combined therapy.
References
https://www.alzheimers.org.uk/about-dementia/types-dementia/alzheimers-disease
https://www.biospace.com/article/potential-for-an-alzheimer-s-treatment-is-closer-now-than-ever