Debilitating and dreaded, dementia elicits a reaction similar to that of cancer. It inflicts its wrath upon millions of individuals each year, with the number on an exponential rise. In these times, people are living longer and the risk of Dementia increases drastically as individuals age. Loss of cognitive functioning is the basis of Dementia. While there are many different forms of Dementia, the most common is Alzheimer’s Disease. Alzheimer’s is a neurodegenerative disease that slowly destroys a person’s memory, thinking ability, and even simple motor functions. No current treatments are available on the market that are capable of slowing down the progression of the disease; the pharmaceutical approach is meant to deal with the symptoms of Alzheimer’s Disease. Thankfully, new scientific innovations are bringing hope to individuals suffering with the disease.
Alzheimer’s disease was discovered back in the early 1900’s by Dr. Alois Alzheimer, who the disease is named after. He discovered the disease upon completion of an autopsy on a patient of his that had been behaving abnormally with ever increasing bouts of loss of memory (1). During the autopsy, he noted shrinking of the cortex and the presence of plaques. A diagnosis of senile dementia was concluded, later to be known as Alzheimer’s.
Memory loss and decline in cognitive function is the basis of dementia, and Alzheimer’s accounts for over half of dementia cases. Alzheimer’s Disease (AD) “is defined by the presence in the brain of neuritic plaques containing aggregated amyloid beta (Aβ) peptide and intraneuronal neurofibrillary tangles containing phosphorylated tau proteins” (2). Interference between communication of the neurons is what causes the nerve cells’ death, which is thought to be blocked by the plaque. In AD, tau proteins are unable to stabilize neurons – due to damage as a result of the phosphate – and twist, forming the neurofibrillary tangles (8). The amyloid beta peptide accumulates in the brain due to an imbalance in production of Aβ and the brain’s ability to clear it (2). Aβ has several isomers and their monomer peptides tend to aggregate, resulting in deposits in the brain as amyloid plaques (2). The death of nerve cells, along with a decrease in brain size is observed in Alzheimer’s patients. In AD, the entirety of the brain shrinks. The cortex suffers the most and atrophy occurs within the hippocampus – the reason why memories, old and new are so affected. Lower levels of serotonin, norepinephrine, and acetylcholine are observed in AD patients (8). The lower levels are thought to be the reason behind the plethora of behavioral problems in AD patients. Individuals with Alzheimer’s slowly begin to lose their short-term memory. As the disease progresses, long term memory and physical functioning are affected, eventually leading to death. The disease essentially eats an individual up from the inside.
The causes of Alzheimer’s Disease are unknown, but many hypothesize that is a combination between genetics and the environment. Offspring can inherit three defective genes from their parents that place them at a higher risk of getting Alzheimer’s, specifically early-onset (30-55). The three mutated proteins – mutation in the APP gene on chromosome 21, PS-1 gene on chromosome 14, and PS-2 gene on chromosome 1 – all increase the beta amyloid in the brain (8). In late-onset AD, the most common gene found to increase an individual’s risk was the apolipoprotein E-4 (APOE-4) (8). Besides genetics, conditions like strokes and head trauma place individuals at an increased risk.
An official diagnosis of Alzheimer’s Disease can only be confirmed after an autopsy and examination of brain tissue. The trifecta of buildup of the amyloid plaque, damaged tau proteins, and an extraordinarily small brain can all be seen in an autopsy. Scientists are currently attempting to locate specific biomarkers in an effort to confirm AD in patients while they are still alive. Tests involving cerebral spinal fluid and simple blood tests are in the works. Through cerebral spinal fluid, biomarkers may be present to indicate AD or an increased risk for AD. A study from the University of Gothenburg found that there was an increase in the protein neurogranin in patients specifically with AD (9). The Aβ42, total tau, is the most established biomarker. Low levels of this acts as an early indicator of AD in persons with mild cognitive impairment (10). In a less invasive method, autoantibodies may be used as blood-based biomarkers for diagnosing AD (10). Specific autoantibody binding patterns could be used to diagnose AD. The biomarkers are comprised of various “categories including kinases, potassium channel subunits, ribosomal and mitochondrial proteins, as well as a variety of receptor, adapter, and other accessory proteins, and cytoskeletal components, among others” (10). In testing between a group with mild cognitive impairment and a healthy control group, the biomarker correctly classified between the two groups with an accuracy of 100 percent (10). The biomarkers were 98.5 percent effective at distinguishing different stages of the disease (10). As of right now, diagnosis in a live individual is based off of medical history, age, medical scans, and the elimination of other possible illnesses, until science and medicine catch up and solidify the findings.
AD patients vary in the length and severity of their decline. Patients may survive as little as a year to as long as twenty-five years upon a diagnosis. As of now, once a patient develops the symptoms of AD, they are irreversible. Often times, AD typically is not what kills an individual, but rather infection due to poor and declined health. Pneumonia as a secondary infection after a cold is a deadly killer in AD patients. AD patients are made comfortable, with drugs to help alleviate certain effects of the disease, until they inevitably die from either infection or complications.
There is no current treatment for Alzheimer’s Disease, only temporary alleviation of symptoms. None of the current drugs on the market can stop or even slow down the progression of Alzheimer’s. Many drugs may start off working well to help slow symptoms, but eventually become ineffective. Cholinesterase can be given to increase acetylcholine; however, as the brain lowers its production of acetylcholine, the drug inevitably becomes useless (8). Drugs can be prescribed for behavioral and psychiatric symptoms such as antipsychotics and anti-anxiety drugs to lower agitation. Common drugs are typically risperidone and lorazepam. Alzheimer’s trials for treatments have been increasing in recent years. However, many of these drugs appeared to look promising in their early stages, but as the studies grew, the treatments proved ineffective or harmful.
There is an increasing number of studies on Alzheimer’s and many have attempted to find a way to slow down the disease, but to no avail. A new study promises some hope. Currently in their phase 3 trials, Biogen, the makers of aducanumab, a “human monoclonal antibody selective for aggregated forms of amyloid beta” has been granted a fast-track by the FDA as a result of their early stage data (2). In preclinical studies, mice were injected with aducanumab and seen to have a reduction of amyloid buildup. The study was multi-dose and placebo-controlled with age ranges from 55 to 85. The test groups consisted of individuals with mild to moderate AD. Patients were divided into seven groups, each with eight patients, to receive varying doses of aducanumab. Six patients in a group received the actual drug, while two were given placebos. Aducanumab or the placebo were given in doses of 0.3, 1, 3, 10, 20, 30, and 60mg/kg, once every four weeks for 52 weeks. As the first study on humans, it was conducted to observe the effects, safety, and tolerability of aducanumab in the various doses in human patients suffering with AD.
Every patient had to undergo thorough examinations to determine the possible side effects. A total of fifty-three patients were involved in the study. The highest dose of 60mg/kg was given to three patients; however, dosing at this level ceased as all three of the patients were found to have contracted severe treatment related ARIA-E (amyloid related imaging abnormalities), “the MR signal alterations thought to represent vasogenic edema (VE) and related extravasated fluid phenomena” (2,3). In all three patients, ARIA-E was eventually resolved. In doses of 30mg/kg or less, ARIA was not present in any of the patients. Some side effects presented themselves throughout all dosages, with participants complaining of headache, diarrhea, and upper respiratory tract infection. None of the patients developed anti-aducanumab antibodies. Aducanumab reduced amyloid plaques and slowed memory decline as determined by cognitive tests.
In its 1b PRIME study, patients were given doses of 1,3,6, or 10mg/kg, with a total of 165 patients participating, receiving monthly doses for 54 weeks. A dosage of three and higher significantly decreased amyloid buildup (5). The treatment destroyed A-beta plaques and, after a year, levels had dropped and, for those on the highest dose, almost vanished. The dose attributed to the “success.” The higher the dose, the less amount of amyloid-beta plaques. Those with the drug – in comparison to the placebo – showed less decline on memory tests over the course of a year. It is hypothesized that aducanumab sticks to amyloid beta and triggers microglia to remove the buildup (6).
Not only has Alzheimer’s been studied with industrious scrutiny in the medical profession, it has also become a topic of discourse among millions of nonprofessionals worldwide. due to its debilitating course and the fact that it affects so many individuals, but no treatment has yet to be created. Aducanumab is attempting to be the first by clearing amyloid plaque, a critical player in AD. Its early data appears successful, and in a few years – upon completion of its phase three trials – a new treatment may be available. Treatments will need to be pinpointed in relation to the stage of AD a patient has.
The Alzheimer’s drug trials are known as the graveyard for drugs; hundreds have been tested and all have failed. Scientists have long discussed and disagreed between fighting amyloid plaque or tau protein in helping Alzheimer patients, but now have started to take both into consideration. Another factor is the fact that amyloid beta deposits very early on in the course of the disease, prior to even clinical symptoms (4). While amyloid plaque and tau proteins are correlated to Alzheimer’s, perhaps they might not be causing it after all. AD is a peculiar disease and crucial information is missing that we have yet to learn.
With its ability to create a shell out of a person, Alzheimer’s inflicts its wrath on sufferers of the disease. They forget who their children are, what they have accomplished in their lives, and everything that made them who they are. Many sufferers revert to a childlike disposition, frequently asking where their parents are, when many of them are now the patriarchs and matriarchs of their families. As horrible as this disease is on the sufferer, family members are not spared. They have to watch their loved one slowly disassociate from reality and become someone who they do not know and who does not know them.
Alzheimer’s is an extremely complicated disease. Our current understanding of it is but a minute percentage of what it should be. Many different and complicated factors are involved. Determining what all of them are, as well as the factors causing the disease, will take time. Through scientific progress and innovation, one day we will not only know the cause of Alzheimer’s Disease, but also how to cure it. Aducanumab may be the first successful step in the long process towards reaching this goal.
By Maia Shalev
Reference List
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