On A Quest to Solve the Unsolved
This previous summer, I worked as a Research Analyst intern for a healthcare company, and I have highlighted my previous experiences within an earlier post. Throughout my placement, I worked on compiling two primary systematic literature reviews specific to the study of Alzheimer’s Disease. I wanted to take an opportunity to share newfound insights that our team was able to uncover and divulge on therapeutic interventions that seem to possess significant therapeutic potential. Disclaimer: these insights stem purely from a deep-rooted curiosity prospect and are not medical advice! These are simply developments I am excited to see soon emerge within the field based on current advances in the literature.
Alzheimer’s Disease
Dementia refers to a broad category of diseases that result in a gradual decline in brain functioning. These diseases manifest in similar ways through an observed rising difficulty in various areas of brain functioning: memory, cognition, language, visuospatial orientation, motor system, behaviour, etc. One disease that can present dementia pathology is Alzheimer’s Disease or AD. Most interestingly, this disease is named after Alois Alzheimer, a leading psychiatrist in his field that was the first to accurately report the pathological attributes specific to the condition 100 years ago (!) — quite a remarkable and noteworthy feat.
AD causes an abnormal and exacerbated buildup of protein within and around neurons resulting in their degeneration — this is called neurodegeneration. I will be discussing these proteins in a little more depth to provide details regarding the specific investigations I was responsible for reporting within. I’m merely covering the basics of pathophysiology, biological pathways, etc. within this post. If you’d like a more in-depth examination of this process, then they are covered incredibly well in good depth within this literature article that I highly recommend reading.
The Key Player
There are many components involved in the pathogenesis of Alzheimer’s Disease. One protein is of particular fundamental importance — Amyloid Precursor Protein (APP). Although APP’s exact functional purpose is unknown, APP is mostly thought to contribute to healthy neuron functioning and growth. After it’s working life has come to an end, and like most other proteins that are broken down and degraded after they are unable to function as optimally as they used to, APP must also be broken down. The origins of the emergence of Alzheimer’s Disease are actually linked with changes in this essential metabolic degradation-process of its degradation. See, there are generally two primary pathways through which APP can be processed:
a) APP can be processed sequentially by two enzymes: α-secretase and γ-secretase. These enzymes are part of a normal processing pathway that does not lead to the development of AD because, after this processing, the fragments produced are soluble protein fragments. These fragments are not of concern, as they are simply released into these various processing pathways and do not contribute to any neurotoxic effects.
b) The other processing pathway is slightly different… in a significant way. Instead of α-secretase carrying out the processing, instead, another enzyme, β-secretase, takes over. The reason for this shift is unclear — one reason may be because of changes in gene expression, resulting in increased concentrations of the β-secretase enzyme being expressed over α-secretase. When β-secretase carries out the processing, the fragments are cut differently and possess different chemical groups and orientations. These fragments are no longer soluble, but instead, are ‘sticky’ and can aggregate and clump with one another. Eventually, if these fragments aggregate in large enough concentrations, they can produce large amyloid-beta (Aβ) plaques. These plaques can come in the way of neuron-to-neuron signalling.
Key Player # 2
Interestingly enough, although these processing-biochemical changes have only yet been occurring outside the neuron, the accumulation of the exterior Aβ plaques can initiate changes within the neuron interior by propagating specific pathways. The inside of the neuron is supported by a cytoskeleton framework composed of microtubules. These microtubule networks are essential for transporting nutrients and compounds across the cell. A specific protein: tau, helps to support and stabilize this cytoskeleton network. However, in individuals with AD, these tau-proteins are chemically modified, causing them to dissociate from the microtubule networks. Similar to the Aβ plaques, they will also aggregate with other tau proteins, forming threads and then eventually tangles — these are called neurofibrillary tangles (NFT). These intra-neuronal tangles can also contribute to impaired neuronal functioning.
AD is distinguishable by its distinct pathology: Aβ plaque buildup and NFT accumulation — however, it’s important to acknowledge that other regulatory pathways and processes may also exacerbate these changes within the brain. One of these changes includes imbalances within the brain’s oxidative-stress state. In this state, an upregulated oxidative stress state can increase free radicals’ concentration contributing to the observed pathology phenomena. One study has indicated that brain scans of patients with AD patients display increased numbers of lesions associated with free radical exposure. These radicals can further exacerbate cellular and molecular changes — i.e. changes in protein expression or mitochondrial functioning or changes in inflammatory pathways or even, propagate the production of even more radical species (Christen, 2000).
Although interference within APP processing seems to be of high value within the development of therapeutic targets to treat AD, it’s also clear that targeting these associated biochemical phenomena (i.e. oxidative stress or inflammation) could also be helpful to alleviate AD symptoms and prevent further progression of the disease. My work focused on investigating whether Melatonin and Vitamins & Carotenoid Supplementation Therapy were of any promise.
Vitamin/Carotenoid Therapy
Considering that AD patients have an affected oxidative stress state, this then encouraged researchers to determine whether supplemented antioxidant administration could alleviate these associated symptoms. Such studies have detected lower antioxidant (retinol, Vitamin E, carotenoids) levels in AD subjects compared with control subjects, but not due to malnourishment. Instead, this downregulated antioxidant level is attributable to the compromised antioxidant defence state in AD pathogenesis resulting in the abnormally high use of these compounds to combat the radical-induced damage (Mullan et al., 2017). Studies such as these show a scarcity of endogenous antioxidants to address these high metabolic needs to counteract the free radicals. Thus, more support needs to be allotted towards offsetting this deficit by administering vitamins and carotenoids as a preventative supplement therapeutic intervention. In some studies, some reports indicate that individuals with high levels of vitamin E have a reduced risk of incident AD compared to participants with lower levels (Lopes Da Silva et al., 2014).
Melatonin Therapy
Melatonin therapy has also arisen to be a potential supplementation therapy that may be used to reduce AD severity and progression. It seemed surprising to me initially to consider how a treatment used to treat short-term insomnia could modulate brain functioning and other physiological functions. However, it has been reported that for AD patients that are still cognitively intact and normal upon examination, their diurnal melatonin rhythm is greatly modulated. Upon analysis, their endogenous melatonin levels also are measured to be lower than average. In fact, on par with worsening progression of AD neuropathology, the amount of melatonin measured within the cerebrospinal fluid tends to decrease correspondingly. Although melatonin’s primary purpose is to regulate the circadian rhythm, surprisingly, this compound also possesses radical-scavenging, anti-oxidant and anti-inflammatory effects. This means its administration can help block pro-inflammatory cytokine action and inhibit oxidative processes that could further up-regulate the already abrogated oxidative-stress state. Such intriguing studies that retrieved within our search indicated that melatonin-supplementation could decrease tau-protein chemical modifications, which amounts to healthier neuron functioning. Information from other studies also suggests that early and long-term treatment could also provide anti-Aβ plaque growth effects. Still, these effects may be inhibited if supplementation begins after Aβ formation.
Future Research Needs
However, with all these retrieved research studies, there is still more research that needs to be conducted to retrieve definitively more straightforward and less mystifying results. The issues with the current state of research are due to a few factors:
- It is difficult to determine the most appropriate markers to be used as an indicator of oxidative stress, a key hallmark feature of AD. This may seem like a very fussy minuscule detail to devoting resources over, however, as there isn’t a definitive reason for employing one marker over another, this contributes to inconsistency across the studies measuring the effectiveness of the supplemented therapy. It seems that it would be more useful for studies to employ a combination of OS markers instead to help monitor the therapeutic response effectiveness and compute outcome prediction
- Although most of the studies diligently measure the changes in plasma levels regularly and consistently throughout the course of the study, one endpoint that remains missing is the glaring absence of an initial baseline measurement, which then questions whether participants may have depleted levels of endogenous antioxidants before entering the study, and thus whether the capacity to observe effects within the prescribed timeline will be affected as a result
- Across the studies, there are also a few observable discrepancies and inconsistencies between the study design, i.e. the number of participants between the study groups, the duration of the experiment, as well as importantly, details regarding the treatment therapies. For some studies, although they intend to measure similar outcomes, a single isoform of a vitamin/carotenoid is sometimes administered instead of a mix of various isoforms. This detail is worth acknowledging as the administration of high doses of one isoform versus another may be harmful, resulting in a chemical imbalance instead of deriving potential clinical benefit
These literature reviews shed light on the realization that it’s evident that this topic of investigation now warrants further analysis and discovery. More specifically, there is a need for the completion of a greater volume of clinical studies (especially more randomized clinical trials) to come closer to reaching a resolving and definitive conclusion on the utility of these therapies as well as detailed knowledge on administration-details such as the optimal timing, duration, optimal treatment cocktail makeup, etc. It would be amiss of me not to conclude this post without mentioning a recent meta-analysis published earlier this year, where the study reported that the implementation of a combination of healthy lifestyle habits could reduce AD progression. These lifestyle habits comprise the intake of a high-quality diet and the implementation of healthy physical activity practices, reduced smoking habits, proper sleeping regimes, staying cognitively active, and imposing the intake of light-to-moderate alcohol consumption (Dhana et al., 2020). With these deceptively-confusing diseases that possess a plethora of root causes and an array of interconnected pathways, I suppose the best advice currently would thus be to implement as many healthy lifestyle choices that you can to stop AD progression before it begins. There’s too much that is currently unknown. Too many things are beyond our control. Researchers are working to cure AD … but it is a slow process. I look forward to the day where these efforts will help to bring hope to those in need. For that day to arrive, it’s important to acknowledge that only through research will we develop a better understanding of the disease, and ultimately devise a cure.
Support Alzheimer’s Research:
Sources:
Chen, M. (2015). The maze of APP processing in Alzheimer’s disease: Where did we go wrong in reasoning? Frontiers in Cellular Neuroscience, 9(MAY), 28. https://doi.org/10.3389/fncel.2015.00186
Christen, Y. (2000). Oxidative stress and Alzheimer disease. American Journal of Clinical Nutrition, 71(2), 621S-629S. https://doi.org/10.1093/ajcn/71.2.621s
Lopes Da Silva, S., Vellas, B., Elemans, S., Luchsinger, J., Kamphuis, P., Yaffe, K., Sijben, J., Groenendijk, M., & Stijnen, T. (2014). Plasma nutrient status of patients with Alzheimer’s disease: Systematic review and meta-analysis. In Alzheimer’s and Dementia (Vol. 10, Issue 4, pp. 485–502). Elsevier Inc. https://doi.org/10.1016/j.jalz.2013.05.1771
Mullan, K., Williams, M. A., Cardwell, C. R., McGuinness, B., Passmore, P., Silvestri, G., Woodside, J. V., & McKay, G. J. (2017). Serum concentrations of vitamin E and carotenoids are altered in Alzheimer’s disease: A case-control study. Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 3(3), 432–439. https://doi.org/10.1016/j.trci.2017.06.006
Roychowdhury, S., & Sierra-Fonseca, J. A. (2017). Heterotrimeric G Proteins and the Regulation of Microtubule Assembly. In Cytoskeleton — Structure, Dynamics, Function and Disease. InTech. https://doi.org/10.5772/66929
