Written by Andrew Ni ’26
Edited by Lizzy Zhang '24
After decades of disappointment, we may finally have a breakthrough in the fight against Alzheimer’s disease. While clinical trials combating Alzheimer’s have failed quite remarkably for the past decade, a new approach that takes advantage of the patient’s own immune system may reduce cognitive decline in Alzheimer’s disease and even treat other neurodegenerative disorders.
As the average life expectancy has climbed dramatically in the last century, dementia has risen to become the world’s fifth leading cause of death [2]. Alzheimer’s disease accounts for roughly 70% of these cases, yet its cause still remains a mystery to researchers [3]. In fact, researchers attribute more than 500,000 deaths annually in the U.S. to the disease—six times more than the official number reported by the Center for Disease Control (CDC) and nearly on par with annual cancer deaths [4].
Alzheimer’s disease is an irreversible, progressive neurodegenerative disorder that leads to memory loss, cognitive decline, and ultimately, death. The condition is frequently characterized by the accumulation of two types of proteins in the brain, known as amyloid and tau [5]. Because the build-up of these proteins is some of the first signs of the disease, the leading hypothesis since 1984 has been that Alzheimer’s is caused by a failure to control these proteins. Particular attention has been directed toward the amyloid protein, which accumulates to form large, sticky plaques in the brain. Alzheimer’s amyloid beta plaques can be thought of as a traffic jam on a highway. Just as cars on a highway can become stuck and unable to move, resulting in a traffic jam, amyloid beta proteins in the brain can clump together and form plaques that block communication between nerve cells. This “traffic jam” in the brain disrupts normal brain function and is a hallmark of Alzheimer’s disease. Consequently, a majority of research efforts have gone into clearing these plaques.
However, it has become abundantly clear that the current approach is not working. In just 2022, the U.S. National Institutes of Health (NIH) spent $3.2 billion on Alzheimer’s research [6]. Despite this overwhelming amount of funding, the failure rate of drug development for Alzheimer’s is near 99 percent [7]. Alzheimer’s is not only a huge burden on society, but its slow, brutal erasure of memory is a devastating experience for both patients and families. As of today, the only FDA-approved Alzheimer’s drug, aducanumab, fails to improve cognitive function and only induces harmful inflammation in the brain.
Fortunately, one team of scientists has recently created an inflammation-free antibody treatment using fusion proteins [8]. For years, researchers around the world have been working on developing new approaches to better understand how inflammation contributes towards progressive neurodegeneration associated with Alzheimer’s. Inflammation plays an important role in several diseases including heart disease, cancer, and diabetes, so it makes sense that inflammation may also contribute to the cognitive decline associated with Alzheimer’s disease.
In line with these new theories, this research team hypothesized that the detrimental effects of amyloid-β may be a consequence of resultant neuroinflammation and not necessarily the formation of plaques. Indeed, in the early 2000s, clinical trials to treat Alzheimer’s were halted due to severe inflammatory side effects. While lowering amyloid-β in an Alzheimer’s mice model using active or passive immunization prevented the death of neurons, this approach failed abysmally in humans due to severe neuroinflammation.
Thus, the team set out “to develop an alternative immunotherapeutic approach that enables Aβ clearance without triggering inflammation.” [9]. With the goal of keeping inflammation in check, the researchers identified a pathway in the body called efferocytosis as a potential target for treatment. Typically, immune responses depend on antibodies to neutralize pathogens such as viruses or bacteria. During this process called phagocytosis, antibodies bind to and activate receptors (Fc receptors) on killer cells which then secrete inflammatory factors to prevent further infection. However, in the delicate organ that is the brain, excessive inflammation from this mechanism may instead damage neurons. In contrast, efferocytosis can bypass this mechanism. Efferocytosis is a mechanism the immune system uses to eliminate millions of dead cells that are produced in the human body every second. Specifically, some receptors on the surface of immune cells (TAM receptors) can identify dead cells through bridging ligands such as GAS6. This is a much better clearance mechanism for Alzheimer’s treatment because, in contrast to phagocytosis, efferocytosis using this pathway produces anti-inflammatory signals.
Nevertheless, normal GAS6 ligands in the body do not recognize amyloid-β. Thus, the scientists needed to develop a new version of GAS6 able to recognize amyloid-β by swapping out the sequence essential for identifying dead cells for the variable-region sequence from aducanumab. In contrast to anti-Aβ antibodies, this new fusion protein, called αAβ–Gas6, facilitated robust absorption of amyloid-β without any signs of inflammation or neurotoxicity. Treatment with αAβ–Gas6 reduced amyloid-β and prevented microglial synapse removal in mice models of Alzheimer’s. As an added bonus, whereas Fc receptors in phagocytosis are expressed mostly by microglia, TAM receptors are found on both microglia and astrocytes meaning double the combat force. These results were published in Nature journal and suggest that GAS6 fusion proteins may be a viable alternative to current Alzheimer’s disease treatments that uses the patient’s own immune system to fight Alzheimer’s [8].
Even better, this discovery is promising for the field of neurodegenerative diseases as a whole. Fusion proteins like this could be used to develop inflammation-free drugs to remove protein aggregates in diseases like Parkinson’s (α-synuclein) and Huntington’s (huntingtin), where there are currently no effective treatments. In fact, after this study, Professors Kim and Chung founded “Illimis Therapeutics” to further develop Gas6-fusion proteins to treat other neurodegenerative diseases [10]. The GAS6 fusion protein engineered by this team of scientists may very well be the golden bullet to a wide array of autoimmune disorders without any concerns of deleterious inflammation. While a lot of research remains, work such as this is what gives us hope in the unyielding battle against neurodegenerative disorders.
References
[1]Mackenzie D. We may finally know what causes Alzheimer’s – and how to stop it [Internet]. New Scientist. New Scientist; 2020 [cited 2022Dec10]. Available from: https://www.newscientist.com/article/2191814-we-may-finally-know-what-causes-alzheimers-and-how-to-stop-it/
[2] Alzheimer’s disease [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2022 [cited 2022Dec10]. Available from: https://www.cdc.gov/dotw/alzheimers/index.html
[3] Dementia [Internet]. World Health Organization. World Health Organization; [cited 2022Dec10]. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia
[4] New Study puts annual Alzheimer’s deaths on par with cancer [Internet]. UsAgainstAlzheimer’s. [cited 2022Dec10]. Available from: https://www.usagainstalzheimers.org/press/new-study-puts-annual-alzheimer%E2%80%99s-deaths-par-cancer
[5] Breijyeh Z, Karaman R. Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules. 2020;25(24):5789.
[6] Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) [Internet]. National Institutes of Health. U.S. Department of Health and Human Services; 2022 [cited 2022Dec10]. Available from: https://report.nih.gov/funding/categorical-spending#/
[7] Cummings J, Reiber C, Kumar P. The price of progress: Funding and financing Alzheimer’s disease drug development. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2018Jun13;4(1):330–43.
[8] Jung H, Lee SY, Lim S, Choi HR, Choi Y, Kim M, et al. Anti-inflammatory clearance of amyloid-β by a chimeric gas6 fusion protein. Nature Medicine. 2022;28(9):1802–12.
[9] Toward inflammation-free therapeutics in Alzheimer’s disease. Nature Medicine. 2022Sep8;28(9):1765–6.
[10] Sterling J. Novel Alzheimer’s therapy without inflammatory side effects [Internet]. GEN. Genetic Engineering & Biotechnology News; 2022 [cited 2022Dec10]. Available from: https://www.genengnews.com/topics/translational-medicine/novel-alzheimers-therapy-without-inflammatory-side-effects/