If History Repeats Itself (Paper 3, part 1)
Alzheimer’s disease (AD) is a neurodegenerative disorder that accounts the majority of all cases of dementia. Over 5 million Americans are living with Alzheimer’s disease today and that number is estimated to nearly triple by the year 2050 due to our aging population. AD is one of the only leading causes of death in the United States that cannot be prevented, cured, or significantly slowed. Therefore, there is a large global market for AD treatments that the healthcare consulting firm GlobalData has estimated to be worth nearly 13 billion dollars by 2023. This creates a strong incentive for pharmaceutical companies to research potential therapies, but there is a high risk in spending so much on AD research. The main issue is that the science behind Alzheimer’s disease is not currently advanced enough for pharmaceutical companies to spend upwards of 1.3 billion dollars on research and development of a new drug. However, several companies such as Merck and Eli Lilly have new medications undergoing phase 3 clinical testing that will surely come to the market in the near future. These drugs are already labeled as potential “blockbuster” medications, which is troubling because no one even knows for sure what causes AD.
The pathological hallmarks of AD are the buildup of amyloid-beta plaques, the formation of neurofibrillary tau tangles, and neurodegeneration. These hallmarks have been associated with developing the disease, but it is unclear what exactly causes it. These new drugs coming to the market are known as BACE inhibitors, which focus on one hallmark, amyloid-beta build up. Their mechanism of action involves inhibiting the enzyme beta-secretase 1. This enzyme cleaves amyloid precursor protein in a way that facilitates its misfolding into amyloid-beta, which then aggregates into neurotoxic plaques. The idea behind this drug is that inhibiting the BACE enzyme will slow the deposition of amyloid-beta and provide the opportunity to properly clear it from the brain by means of the microglial immune response or other mechanisms. This therapy seems like a viable option, but there are several potential issues with this treatment.
One problem is that the effectiveness of these drugs depends on the validity of the amyloid hypothesis, which states that AD is caused by the build up of the neurotoxic peptide amyloid-beta. In the brains of AD patients, amyloid is deposited and cleared away, but eventually deposition of amyloid begins to outweigh the clearance leading to the formation of plaques, synaptic dysfunction, and eventually neuronal death. It is unclear exactly how amyloid-beta would cause neuronal death, however, some believe that it may disrupt calcium ion homeostasis leading to the induction of apoptosis. There is substantial evidence supporting this theory, but if this theory is incorrect then these drugs being portrayed in the media as potential miracle cures would be useless.
Another potential issue is that there is a possibility that once amyloid plaques form and the damage is done, clearing the amyloid-beta may not have much of an effect on the clinical symptoms. Although this could be a viable option for preventing further progression of the disease, it would not be able to reverse any memory loss that has already occurred. If this is true, then the media reports of these new drugs potentially curing Alzheimer’s disease may help to mislead patients. Since the science of AD is still in its infancy, it is imperative that doctors and patients view any emerging AD drugs with health skepticism.
Years ago, a similar sequence of events occurred when the scientific community largely believed in the cholinergic hypothesis which produced a line of research that resulted in many new medications that are on the market now. The cholinergic hypothesis stated that AD was caused by a deficiency in the neurotransmitter acetylcholine which is vital for enhancing long term potentiation and regulating other processes of learning and memory. There are currently four drugs on the market that target cholinesterase and all of these drugs have significant side effects such as nausea, vomiting, diarrhea, dizziness, headaches, and more. However, none have been able to produce any clinically significant benefits to AD patients. Therefore, most patients stop using these medications after several months of receiving no therapeutic benefits. When these drugs failed to provide substantial benefits, the scientific community lost their support of the cholinergic hypothesis. If history repeats itself with the amyloid hypothesis, then the next generation of AD patients will likely suffer unnecessary negative side effects from these drugs without any therapeutic benefits.
