While
many other diseases take a person’s life, there’s also a few ones which gradually
steal life away while a person is still technically alive & functioning,
Alzheimer’s is one of the latter type. We all probably have seen the movie ‘The
Notebook’, where we see how a dear one, suffering from Alzheimer’s disease
becomes a total stranger. Even if we haven’t personally known an Alzheimer’s
patient, we can imagine the pain & sufferings undergone by the patients
& their families. According to a report sponsored by WHO in May 2018,
Alzheimer’s is one of the leading causes of death, contributing to more deaths
than cancer, diabetes, tuberculosis & road accidents.1
As the most common form of
dementia, Alzheimer’s disease is a neurodegenerative disease that is
characterized by accumulation of extracellular amyloid beta plaques &
intracellular neurofibrillary tangles. Recent studies support the
idea that the accumulation of amyloid beta (Aβ) in brain is caused by an
imbalance between the production and clearance of Aβ.2 The most common symptoms of the disease are: memory
loss, confusion, mood swings, disorientation and in severe cases death of brain
cells & loss of brain activity leading to death.
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Figure 1. A
schematic of brain cells of a healthy patient (left) and one diagnosed with
Alzheimer’s disease.3
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Scientists have been looking for antibody-based immunotherapy against Aβ
(Amyloid β) to enhance the clearance or reduce the neurotoxic effects of Aβ
plaques. Aducanumab is a human monoclonal antibody that selectively targets Aβ
plaques. Aducanumab can enter the brain by crossing the blood brain barrier. Once
inside the brain, Aducanumab binds parenchymal Aβ, and reduces the extent of Aβ
plaques. Aducanumab was developed using the human memory B cells. Human memory
B cell is known to be active against the aggregation of β-amyloid. The methodology
used involved screening the human memory B cells to identify antibodies that
selectively binds the aggregated forms of β-amyloid. The antibodies were then cloned and sequenced
to develop the recombinant form, the drug Aducanumab.4
Aducanumab reduces brain Aβ plaques in a dose- and time-dependent manner
in patients with prodromal or mild Alzheimer’s.4 Placebo & 3
different doses of 3mg/kg, 6mg/kg, 10mg/kg were administered intravenously
every month in 165 patients in 33 sites of USA over the course of 1 year. The
results came out fairly positive, showing significant reduction in the Aβ
plaques. A comparative study of brain scan images of Alzheimer’s patients before
and after the treatment is given in Figure-2. Common side effects of the
treatment were ARIA (Amyloid related imaging abnormalities), headache, UTI
(Urinary tract infection) & upper respiratory tract infection.
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Figure 2. PET (Position Emission Tomography) images of the Alzheimer’s
patients before and after Aducanumab treatment. Red color indicating the
plaque.4
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Though many more steps and trials are required to finally approve the
drug for its intended use, it’s very encouraging that we may finally have a
treatment for Alzheimer’s disease that after decades of efforts. So, it can be
hoped now that in a few years, there will be a drug to use against Alzheimer’s
disease which will save many lives &
bypass a significant amount of
sufferings. It seems like the prayers of Alzheimer’s patients &
their families are finally answered.
References:
- World Health Organization (WHO), web accessed on 9/25/2018
- Kristin R Wildsmith, Monica Holley, Julie C Savage, Rebecca Skerrett and Gary E Landreth (2013). “Evidence for impaired amyloid β clearance in Alzheimer’s disease”. Alzheimer’s Research & Therapy. 5:33
- Hooper NM (2005). “Roles of Proteolysis and Lipid Rafts in the Processing of the Amyloid Precursor Protein and Prion Protein”. Biochemical Society Transactions. 33(Pt 2):335–38
- Jeff Sevigny, Ping Chiao, Thierry Bussière, Paul H. Weinreb, Leslie Williams, Marcel Maier, Robert Dunstan, Stephen Salloway, Tianle Chen, Yan Ling, John O’Gorman, Fang Qian, Mahin Arastu, Mingwei Li, Sowmya Chollate, Melanie S. Brennan, Omar Quintero-Monzon, Robert H. Scannevin, H. Moore Arnold, Thomas Engber, Kenneth Rhodes, James Ferrero, Yaming Hang, Alvydas Mikulskis, Jan Grimm, Christoph Hock, Roger M. Nitsch2, Alfred Sandrock (2016). “The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease”. Nature. 53: 50-57By Iris Begum, a PhD student in Chemistry at the University of Kentucky
This area of research is expanding rapidly; I was not aware of how prevalent Alzheimer’s disease has become. It is quite difficult to create a promising treatment drug, as there are different forms of amyloid beta plaques and multiple stages of progression of the disease. A large downfall of monoclonal antibody treatment is the high cost and need for repeated injections – it may not be feasible for patients to get the treatment they need.
ReplyDeleteA 2017 article comparing studies of different immunotherapy efficacies did not show significant treatment improvements for any of the drug therapies listed. Of the ones tested, however, Aducanumab showed the most promise for continuing clinical trials, “which demonstrated substantial reductions in brain fibrillar Aβ in an early-phase study, accompanied by slowing of clinical decline at higher doses”.1
The vaccination treatments of Aducanumab have shown to help clear aggregates in the oligomer and fibril form, but not in the monomer form; the vaccine has also been tested in cases of mild AD, but not yet in populations of patients with moderate to late stages of Alzheimer’s1. The amount of information still unknown about this monoclonal antibody vaccine calls for further studies to be conducted.
If amyloid beta protein aggregates are one of the major causes behind Alzheimer’s disease, is there a way to prevent these clusters from forming in the first place?
1. Dyck, C. H. (2018). Anti-Amyloid-β Monoclonal Antibodies for Alzheimer’s Disease: Pitfalls and Promise. Biological Psychiatry, 83(4), 311-319. doi:10.1016/j.biopsych.2017.08.010
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ReplyDeleteAs mentioned, Alzheimer's Disease research is a huge topic in the scientific community. Unfortunately, it seems as though everyone seems to know someone who has been affected by this horrible disease. It's very interesting that this new drug Aducanumab has been developed and has shown to reduce the amyloid beta plaques in the brain. The death of brain cells cannot be reversed, which is why there is no current cure for Alzheimer's disease. There are only approved medications to reduce the symptoms and help improve patient's quality of life.
ReplyDeleteI was wondering which drugs are approved for patients suffering from Alzheimer's and came across several cholinesterase inhibitors. These drugs include: Aricept, Exelon, Razadyne and Namenda (Legg, 2018). Cholinesterase inhibitors work by preventing the breakdown of acetylcholine, which is an important neurotransmitter involved in learning and memory (Alzheimer's Association, 2016). These drugs help regulate the activity of glutamate, which is an important chemical involved in information processing (Alzheimer's Association, 2016). By utilizing these cholinesterase inhibitors, communication between nerve cells in the brain is supported.
While these treatments are expensive and time-consuming, the research is paramount. With many of the "baby boomer" generation advancing in age, finding a cure for Alzheimer's is becoming more important than ever. Are there certain genes that have been implemented in the diagnosis of Alzheimer's?
References:
Legg TJ. What's To Know About Alzheimer's Disease? Medical News Today. https://www.medicalnewstoday.com/articles/159442.php. Published February 13, 2018. Accessed October 16, 2018.
Medications For Memory. Alzheimer's Association. https://www.alz.org/alzheimers-dementia/treatments/medications-for-memory. Published 2016. Accessed October 16, 2018.
This is a pretty interesting development in our fight against Alzheimers. I still remain, however, somewhat skeptical if clearing the amyloid plaques will restore any of the cognitive deficits or behavioral changes. There’s still a debate over whether the amyloid plaques are the cause of the disease or merely a characteristic/ symptom. Numerous animal studies indicate that clearing the plaques may not necessarily cure the disease. The longitudinal nun study from 1986 shows that despite the presence of plaques and tangles and brain shrinkage, the nuns’ brains showed no signs of having the disease while they were alive. For now, our best bet against Alzheimer’s is to lead a healthy and active lifestyle, developing new habits and staying curious. I’ve attached a link to a great TED talk below, do check it out.
ReplyDeleteWhat can you do to prevent Alzheimer’s?
https://www.ted.com/talks/lisa_genova_what_you_can_do_to_prevent_alzheimer_s#t-491524
Nuns Offer Clues to Alzheimer's and Aging.
https://www.nytimes.com/2001/05/07/us/nuns-offer-clues-to-alzheimer-s-and-aging.html
I knew Alzheimer’s disease, as well as finding a cure is a big focus but something new I learned was that it was the leading cause of death, even more than cancer, diabetes, TB, and road accidents. After reading this blog, I was curious on whether there were other ways to increase the clearance of amyloid beta (AB) in patients with Alzheimer’s disease (AD).
ReplyDeleteI found a study from 2016 finding a correlation between neuronal heparan sulfates and promoting amyloid pathology by regulating the clearance of AB (Liu et al., 2016). The first critical step in the pathogenesis of AD is the accumulation of AB peptide within the brain (Liu et al., 2016). When looking at patients with late-onset AD, studies have shown that AB clearance is often compromised (Liu et al., 2016). This accumulation leads to the development of a large sum of AB, which harm synapses and will conclude at neurodegeneration (Liu et al., 2016). All cell types, such as neurons contain heparan sulfates (HS) on the cell surface (Liu et al., 2016). HS have appeared in the pathogenesis of AD and play a major role in the large sums of AB that appear (Liu et al., 2016). Researchers in this study used conditional deletion and removed the Ext1 gene, in which translates for glycosyltransferase, needed for the biosynthesis of HS (Liu et al., 2016). They examined postnatal neurons of APP/PS1 mice and found a decrease in AB oligomerization and removal of amyloid plaques (Liu et al., 2016). They also found an increased rate of AB clearance in the brain interstitial fluid (ISF), which proposed that neuronal HS either inhibited or signified an ineffective AB clearance pathway (Liu et al., 2016). However, they did find various increased amounts of HS proteoglycans (HSPG’s) within AD patients’ postmortem brain tissues (Liu et al., 2016). They believed that the increased amount proposed that this particular pathway could be correlated with amyloid pathogenesis (Liu et al., 2016). Liu et al., 2016, believed that their breakthrough offers awareness in therapeutic mediations that should target AB-HSPG interactions in patients with Alzheimer’s disease.
Reference:
Liu, C., Nhao, N., Yamaguchi, Y., Cirrito, J. R., Kanekiyo, T., Holtzman, D. M., & Bu, G. (2016). Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer’s disease. Sci Transl Med. doi:10.1227/neu.0000000000001291
As many of you mentioned above, there is a great deal of ongoing research on the treatment of Alzheimer's disease in hopes of one day finding a cure. However, another notable approach to tackling the problem of Alzheimer's is by looking at prevention methods. Delaying the onset of the disease or possibly preventing it altogether would be an ideal solution. However, it is difficult to study preventative measures primarily because the underlying pathology of a chronic disease such as Alzheimer's likely develops well in advance of the occurrence of noticeable symptoms of the disease. Based on a review of four reviews from the Minnesota Evidence-based Practice Center (EPC) published in Annals, it is clear that our current knowledge of the disease pathology and what may work as preventative measures is significantly lacking. These studies looked at strategies such as physical activity, cognitive training, supplements, and pharmacological treatments for preventing the onset of dementia. The evidence, though inconclusive, was somewhat promising and indicated that more research ought to be done on these topics. Based on our current knowledge, it seems that the best strategy is to promote common-sense actions and healthy life choices to reduce some of the risk of preventing Alzheimer's.
ReplyDeleteReference:
Larson, E. B. (2017). Prevention of Late-Life Dementia: No Magic Bullet. Annals of Internal Medicine, 168(1), 77. doi:10.7326/m17-3026
I agree with Satya in that once the amyloid plaques have already formed, the neurocognitive damage has most likely been done. This topic is also related to what we discussed in class on the 24th. Often, treatment begins too late for Alzheimer's patients and instead of actually treating the disease, we are managing the behavioral symptoms. Also, we spoke about Alzheimer's in my human disease class last semester, and there is still debate in the field as to whether the amyloid plaques are the main issue. Yes, they are most likely neurotoxic, but some researchers believe that the neurofibrillary tangles are the main issue. It has been shown that the number of tangles is more closely related to the degree of dementia the patient is suffering from (Brion, 1998). Hopefully, there will be techniques developed that allow us to detect amyloid plaque and neurofibrillary tangle formation early on, so that treatments such as aducanumab can be used.
ReplyDeleteReference:
Brion, J. (1998). Neurofibrillary tangles and Alzheimer's disease. European Neurology, 40(3), 130-140.
Wow this sounds incredibly promising. Even if you could just stop the disease from progression that's a win. Maybe in combination with other therapies some neurocognitive function could then be regenerated.
ReplyDeleteAs Katie and Satya talked about, at this moment, brain cell death and cognitive impairment cannot possibly be reversed in patients with AD. The Alzheimer's Association is currently researching, looking for a bio-marker for AD that could potentially save lives. Alzheimer's has been found to shrink the brains of victims dramatically, so brain imaging such as MRI, CT, and PET scans would make effective tools in finding out if a person's brain has begun showing signs of AD.
ReplyDeleteTaking a genetic profile of people at a young age, in order to inform them if their genes increase their risk for developing AD could also help decrease the incidence of new cases. It is unfortunate that no true leads have been discovered at this point to unravel the mystery that is AD. All that can be done at this point is to lower chances of AD is to live a healthy life as, Cassie pointed out.
Alzheimer's is a terrible disease, something my family knows all too well after watching my granddad suffer from it. In Lisa Genova's TED talk that Satya linked, she gave good general information. At the beginning of her talk, she had everyone look at two people and told them that if they all lived to age 85, one of them would have Alzheimer's disease. If they weren't the individual who had it, they would likely be a caregiver. The audience found this striking and I think it really showed the prevalence and impact of AD. Plaques begin to form around 40, but symptoms do not appear for another 15-20 years (reflecting what we learned about brain diseases last week). Because the cognitive damage cannot be undone, the true cure will likely be preventive. Like Cassie pointed out, it is difficult to identify preventive measures other than general healthy lifestyle choices. Regular exercise is important, as there has been a strong correlation between AD and cardiovascular disease. I found it interesting that a healthy sleep schedule could also help. During deep sleep, our brain clears out Aβ plaques using microglial cells. Another way to lower our risk for AD is through cognitive reserve, by creating more synapses. Cognitive reserve may be a strong explanation for the longitudinal nun study. By having more synapses, there is a way for the brain to remain functioning despite the plaques, a buffer. This comes with rich higher learning, like learning a new language or reading a book, not just simple recall.
ReplyDeleteI think it's really interesting that immunotherapy is being engineered for treatment of AD. I did not even know it existed before this class, and it was awesome to learn about its success with cancer. The treatments for both diseases have their unique differences and they both have a long way to go. It makes me wonder what else immunotherapy could be used to treat.
I think that early detection and intervention methods would be better than having to deal with reversing the damage already done. This is especially relevant after talking in class about the progression of disease and that we can manage diseases, or even treat them, more efficiently if caught at an earlier stage. However, I think non-traditional methods of treatment are always fascinating and could lead to advances that may not be readily apparent. One that I always reference when speaking with people in public is the use of cocaine for treating Parkinson's disease (Friedman & Chang, 2013). One interesting early intervention method that I found for Alzheimer's was the use of the curcumin plant, which is the plant that provides tumeric (Kelley & Knopman, 2009). There is evidence that suggest that the cholesterol lowering capacity of the plant within the brain aids in the prevention of amyloid plaque buildup, which is an easy and safe alternative to some medications given the relative safeness of the plant (Kelley & Knopman, 2009). My point is that I think it would be a good idea to research non-traditional methods of treatment, although it may be difficult with the restrictions we have in place. Especially when working with a controlled substance, such as Cocaine.
ReplyDeleteReference:
Friedman, J. H. & Chang, V. (2013) Crack cocaine use due to dopamine agonist therapy in Parkinson disease. Neurology, 80(24): 2269-2270.
Kelley, B. J. & Knopman, D. S. (2009) Alternative Medicine and Alzheimer's Disease. Neurologist, 14(5): 299-306
As mentioned previously, the majority of drugs currently on the market for the treatment of Alzheimer's disease aim to alleviate symptoms or slow the progression of the disease as death of brain cells is irreversible. Because of this, early detection of AD is paramount. In a 2013 study, researchers designed a simple and cost-effective diagnostic test for early detection of AD by comparing the distance in cm at which peanut butter could be smelled through the right vs left nostrils. (1) Olfactory deficits are common in AD patients as portions of the olfactory cortex are some of the initial sites of AD pathology with greater degeneration shown in the left hemisphere than the right. (1) Of their participants, those with a confirmed diagnosis of early stage AD or mild cognitive impairment had significantly more trouble smelling the peanut butter, and generally those participants were able to smell peanut butter 10cm farther away using their right nostril than their left nostril. (1) Unfortunately, a 2014 study was unable to replicate the results. (2) Further research is certainly warranted into this test along with the development of other early detection methods.
ReplyDelete1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823377/
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167392/
Although brain cell death cannot be repaired and neurocognitive impairment may not have the ability to regain function post-damage, maybe we should take a different approach such as early diagnosis and preventing symptoms such as memory loss? Alzheimers.net explains the focus on Alzheimer's prevention rather than treatment by stopping Alzheimer's before the disease starts rather than mitigate it's symptoms after onset. Alzheimer's is such a devastating disease because it is a progressive brain disease that essentially slowly erases a person little by little until it reaches the point of fatality. The sad truth is that there are no Alzheimer's survivors. Maybe if we can start by researching prevention strategies and reducing symptoms, we can improve the quality of life while also learning more about the disease.
ReplyDeletehttps://www.alzheimers.net/better-alzheimers-prevention-with-early-detection/
https://www.livescience.com/55218-alzheimers-death-pat-summitt.html
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