글로벌 트렌드내서재담기 

책표지






  • Alzheimer’s Research Reaches a Tipping-Point

    Today, Alzheimer’s disease affects over 50 million people worldwide. Its symptoms include progressive memory loss as well as impaired movement, reasoning, and judgment. And while Alzheimer’s disease affects the brain 20 years or more before symptoms appear, patients typically seek medical attention and are diagnosed only when they begin having memory problems.

    Notably, the problem will get far worse if we don’t find a treatment or a preventive method. In the U.S., Alzheimer’s disease now afflicts more than 6 million people and the Alzheimer’s Association estimates that their care now costs $355 billion a year. Furthermore, the U.S. mortality rate from Alzheimer’s in the overall population significantly increased from 16 to 30 deaths per 100,000, between 1999 and 2019. That’s an 88% increase!

    Speaking at the AAIC 2021 conference, researchers from the University of Washington School of Medicine reported that the number of people with dementia worldwide is estimated to nearly triple by 2050, reaching more than 152 million.

    And unlike most catastrophic maladies which affect large numbers of people in developed countries, doctors are unable to diagnose, prevent, treat or even explain its causation in a pragmatically useful way. However, that has not stopped thousands of researchers around the world from working on the problem. And it increasingly seems that all of that work is about to pay off.

    As a starting point, researchers at Boston University School of Medicine recently asked, “what percentage of dementia cases are severe and what percentage are moderate or mild.” They found that 50.4 percent of cases are mild, 30.3 percent of cases are moderate and 19.3 percent are severe.

    Other research indicates that personality traits play a role in determining whether we develop dementia. Researchers at the University of California San Francisco used innovative statistical methods to predict the average trajectories of depressive symptoms for approximately 15,000 participants ages 20 to 89, divided into three life stages labeled older, midlife and young adulthood.

    They then applied these predicted trajectories and found that in a group of approximately 6,000 older participants, the odds of cognitive impairment were 73 percent higher for those estimated to have elevated depressive symptoms in early adulthood, and 43 percent higher for those estimated to have elevated depressive symptoms in later life. Several mechanisms explain how depression might increase dementia risk.

    One explanation is that hyperactivity of the central stress response system increases production of stress hormones called glucocorticoids; this excess of hormones damages of the hippocampus, the part of the brain essential for forming, organizing and storing new memories. With up to 20 percent of the population suffering from depression during their lifetime, it’s important to recognize this as a risk factor related to dementia.

    In other recent research, scientists at UNLV discovered that chronic hyperglycemia, found in people with poorly treated diabetes, impairs working memory performance and alters fundamental aspects of working memory networks contributing to Alzheimer’s disease.

    Why?

    The researchers found that two parts of the brain that are central to forming and retrieving memories - the hippocampus and the anterior cingulate cortex - became over-connected, or hyper-synchronized due to hyperglycemia. While the research is still ongoing, it clearly points toward another reason diabetic and prediabetic individuals need to carefully control their blood sugar.

    Researchers at Australia’s Bentley University discovered a potentially more important causal factor related to Alzheimer’s: Amyloid protein made in the liver can cause neurodegeneration in the brain. Since Amyloid protein is thought to be a key contributor to development of Alzheimer’s disease, the results suggest that the liver may play an important role in the onset or progression of the disease.

    The abundance of toxic protein deposits in the blood, originate in the liver, and this could be addressed through a person’s diet as well as drugs that specifically target lipoprotein amyloid. Such a liver-focused regimen could potentially slow the progression of Alzheimer’s disease.

    Sleep is another lifestyle factor that may help prevent Alzheimer’s Disease. Multiple studies in humans and mouse models indicate that sleep disruptions raise the risk of Alzheimer’s disease by increasing the accumulation of disease-relevant proteins such as amyloid-beta in the brain.

    In a new study, researchers at Baylor College of Medicine discovered that restoring normal sleep reduces the accumulation of amyloid-beta plaques in the brain by returning a brain center called the thalamic reticular nucleus to normal operation. Since sleep disturbances can be due to unrelated causes, such as obstructive sleep apnea or restless leg syndrome, addressing sleep-related risks may require dealing with secondary conditions.

    2021 was also a big year in terms of developing techniques for the early diagnosis of Alzheimer’s disease. Historically, Alzheimer’s disease has been detected via cognitive tests or brain scans, which are useful only after impairment begins and it’s too late for prevention.

    However, research recently published, by a Hong Kong-based research team, in Alzheimer’s & Dementia: The Journal of the Alzheimer’s As – sociation, documented tests of a simple but robust blood test for early detection and screening of Alzheimer’s disease with an accuracy level of over 96%. The new test uses a panel of 19 biomarker proteins to identify those who will develop Alzheimer’s disease years in the future.

    Beyond this increased understanding of how the disease works and how to detect it, there were several very promising discoveries in 2021 on the prevention and treatment fronts. Some of these involved surprising dietary approaches while some others involved repurposing medications already approved for other diagnoses. Meanwhile, a few involved entirely new therapies.

    Consider some of the important dietary discoveries.

    According to researchers at the University of Barcelona, lifestyle and diet are decisive as a strategy for preventing cognitive deterioration and its progression in Alzheimer’s and other dementias. The 12-year study published in the journal Molecular Nutrition and Food Research, found that higher intake of fruits, vegetables and plant-based foods provides polyphenols and other bioactive compounds that could help reduce the risk of cognitive decline due to aging. 

    These results revealed an association between preventing cognitive impairment in the elderly and metabolites derived from cocoa, coffee, mushrooms, red wine, and polyphenol-rich foods such as apples, cocoa, green tea, blueberries, oranges and pomegranates.

    Similarly, a diet rich in essential amino acids can help prevent Alzheimer’s Disease. Using a mouse model of Alzheimer’s disease, Japanese researchers have shown that the intake of a specific set of amino acids can inhibit the death of brain cells, protect the connections between them, and reduce inflammation, preserving brain function. Their research suggests that this amino acid combination called Amino LP7 can hinder the development of Alzheimer’s disease.

    Additionally, Australian researchers have discovered that people who drink a higher-than-normal amount of coffee were less likely to develop Alzheimer’s later in life. The study published in the journal Frontiers in Aging Neuroscience , appears to show that this is due to the combination of caffeine and other molecules found in coffee. Another study published in PLOS Medicine, showed that drinking 4-6 cups of coffee or tea each day reduced strokes as well as cognitive impairment.

    A preclinical study published in the journal Frontiers of Aging Neuroscience suggests that Fenchol, a natural compound abundant in some plants including basil, can help protect the brain against Alzheimer’s disease pathology. In the process, the team from the University of South Florida, discovered a sensing mechanism associated with the gut microbiome that explains how fenchol reduces neurotoxicity in the Alzheimer’s brain. Additional research is needed to determine how this discovery can be most effectively put to work in humans.

    In addition to these and other dietary approaches, repurposing drugs approved for other conditions offers the most immediate prospects for preventing and delaying the onset of Alzheimer’s disease. 2021 was truly a banner year for such discoveries.

    Consider three particularly big breakthroughs in this category.

    First, a new study published in the journal Nature Aging has identified sildenafil, the active ingredient in Viagra, as a promising drug candidate to help prevent and treat Alzheimer’s disease. Researchers at the Cleveland Clinic determined that sildenafil is associated with a 69% reduction in incidences of Alzheimer’s. Furthermore, sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension and type 2 diabetes. Those who already use sildenafil for other conditions, will now have additional reason to use it.

    Second, Japanese scientist found that a relatively inexpensive drug called somatostatin was effective in preventing Alzheimer’s disease in mouse models. The study showed that using somatostatin to block the function of a protein called ENSA reduced physical changes in the brain associated with the Alzheimer’s disease and resulted in improved memory. The researchers believe this therapy could be cheaper and more effective than any treatment currently available. More research is needed before it’s ready for trials in humans. And,

    Third, as explained recently in the journal Nature Aging, researchers have identified bumetanide, a commonly available oral diuretic pill, as a leading drug candidate to be repurposed to treat those at genetic risk of developing Alzheimer’s. The research included analysis showing that those who took bumetanide had a significantly lower rate of Alzheimer’s disease compared to those not taking the drug. The research showed that those who had the genetic risk and took bumetanide had a 35% to 75% lower prevalence of Alzheimer’s disease compared to those not taking the drug.

    The beauty of these three solutions is that they’ve previously completed Phase I clinical trials needed to establish their safety. The primary question is whether they will be proven effective for use in treating Alzheimer’s.

    The final category of breakthroughs involves truly new and original treatments for Alzheimer’s disease which may one day make it as rare as polio or smallpox.

    Consider two of the potentially game-changing discoveries from 2021.

    First, researchers at Albert Einstein College of Medicine have developed a novel drug that shows potential for treating Alzheimer’s, even after symptoms have appeared.

    As explained in the journal Cell , the drug, called CA, works by supporting a cell-cleaning process called CMA. CMA is capable of digesting defective tau and other proteins. But the sheer amount of defective protein in Alzheimer’s overwhelms CMA and essentially cripples it. CA revitalizes CMA efficiency by boosting levels of a key CMA component. Specifically, CA works by increasing the number of so-called LAMP2A receptors on organelles called lysosomes, which recycle defective proteins. Oral doses of CA administered to Alzheimer’s disease mice models over 4 to 6 months led to improvements in memory, depression, and anxiety making the treated animals resemble healthy mice. 

    And the drug significantly reduced levels of tau protein and protein clumps compared with untreated animals. Importantly, Treatment with CA did not appear to harm other organs even when given daily for extended periods of time. The researchers founded a company called Selphagy Therapeutics, which is currently developing CA and related compounds for treating Alzheimer’s and other neurodegenerative diseases. And,

    Second, as explained in the International Journal of Molecular Sciences, Japanese researchers recently discovered a new treatment candidate called SAK3 which appears to not only halt neurodegenerative symptoms of Alzheimer’s disease, but also to reverse the effects of the disorder. 

    In mice, SAK3 administration significantly prevented the progression of neurodegenerative behaviors in both motor dysfunction and cognition, even after the onset of cognitive impairment. The researchers plan to begin clinical trials in humans in the next year.

    What’s the bottom line?

    Alzheimer’s disease is the most disruptive and costly chronic health problem facing humans in the 21st century. In the United States alone, it already destroys millions of lives and care costs at least $355 billion annually. Unless something is done to alter its trajectory its impact will increase dramatically, at least tripling over the next thirty years. 

    This dire situation has driven a dramatic increase in Alzheimer’s-related research over the past 20 years. That rapidly accelerating research is getting us closer to understanding, diagnosing, preventing and treating the disease. As the accelerating pace of research continues, we’re approaching the day when Alzheimer’s disease becomes manageable.

    Given this trend, we offer the following forecasts for your consideration.

    First, during the 2020s, our understanding of Alzheimer’s disease will grow exponentially, opening-up a wide range of new possibilities for diagnosis, prevention and treatment. 

    The past three decades have laid the foundation for enormous breakthroughs in Alzheimer’s research, just as the early work of Louis Pasteur and others laid the foundation for the antibiotic revolution of the 1940s. Genomics, MRIs, animal models of the disease and enormous medical history databases are all finally available for researchers to use.

    Second, reliable, inexpensive and noninvasive tests for Alzheimer’s biomarkers will become widely available by 2030. 

    Today, most people are diagnosed with Alzheimer’s disease based on measurable cognitive decline. But by the time these symptoms are detectable, the disease has already done significant, and currently irreversible, damage. Fortunately, Biomarkers for Alzheimer’s disease appear 10-to-20 years before measurable cognitive decline. That’s when preventative action can still be taken and emerging therapies will be able to do the most good. Expect the trajectory of the disease to change dramatically as soon as such tests become widespread, enabling early intervention.

    Third, as our understanding of Alzheimer’s disease grows, people will pro-actively adopt preventative behaviors sharply reducing the share of the population which develops full-blown cognitive problems. 

    As the latest research affirms, there are many dietary, lifestyle and pharmaceutical interventions which can reduce an individual’s chances of developing Alzheimer’s disease. As people become more aware of these decisions and their implications, behaviors will change and outcomes will significantly improve.

    Fourth, by the end of the 2030s new cases of Alzheimer’s disease will become rare. 

    That’s especially likely if repurposed medications we already know how to cheaply manufacture turn out to be highly effective. Unfortunately, just as victims suffered from the affects of polio long after it was eradicated, individuals and families hit by Alzheimer’s over the next 15 years or so, will suffer the consequences for decades. Our objective as a society should be to deploy diagnosis, prevention and treatment as quickly and as widely as technically and economically possible. And,

    Fifth, the payoff in terms of productivity, reduced costs and human happiness will add tens of trillions of dollars a year to global GDP. 

    As mentioned in trend #2 this month, personal care commitments related to children and the elderly are major contributors to the Great Resignation. As COVID-19 exits the scene, childcare commitments will return to normal, but eldercare responsibilities will only increase until we bring Alzheimer’s disease growth under control. And that’s in addition to the impact of eliminating Alzheimer’s victims exiting the workforce.

    Resource List
    1. PLOS Pathogens. 2021. Emma Nichols & Theo Vos. Estimating the global mortality from Alzheimer’s disease and other dementias: A new method and results from the Global Burden of Disease study 2019.

    2. PLOS Pathogens. 2021. Mohammad Khursheed Siddiqi, Chae Kim, Tracy Haldiman, Miroslava Kacirova, Benlian Wang, Jen Bohon, Mark R. Chance, Janna Kiselar, Jiri G. Safar. Structurally distinct external solvent-exposed domains drive replication of major human prions.

    3. Journal of Alzheimer’s Disease. 2020. Jing Yuan, Nancy Maserejian, Yulin Liu, Sherral Devine, Cai Gillis, Joseph Massaro, Rhoda Au. Severity Distribution of Alzheimer’s Disease Dementia and Mild Cognitive Impairment in the Framingham Heart Study.

    4. Journal of Alzheimer’s Disease. 2021. Willa D. Brenowitz, Adina Zeki Al Hazzouri, Eric Vittinghoff, Sherita H. Golden, Annette L. Fitzpatrick, Kristine Yaffe. Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline.

    5. Communications Biology. 2021. Ryan. A. Wirt, Lauren. A. Crew, Andrew. A. Ortiz, Adam. M. McNeela, Emmanuel Flores, Jefferson. W. Kinney, James M. Hyman. Altered theta rhythm and hippocampal-cortical interactions underlie working memory deficits in a hyperglycemia risk factor model of Alzheimer’s disease.

    6. PLOS Biology. 2021. Virginie Lam, Ryusuke Takechi, Mark J. Hackett, Roslyn Francis, Michael Bynevelt, Liesl M. Celliers, Michael Nesbit, Somayra Mamsa, Frank Arfuso, Sukanya Das, Frank Koentgen, Maree Hagan, Lincoln Codd, Kirsty Richardson, Brenton O’Mara, Rainer K. Scharli, Laurence Morandeau, Jonathan Gauntlett, Christopher Leatherday, Jan Boucek, John C. L. Mamo. Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype.

    7. Alzheimer’s & Dementia. 2021. Yuanbing Jiang, Xiaopu Zhou, Fanny C. Ip, Philip Chan, Yu Chen, Nicole C.H. Lai, Kit Cheung, Ronnie M.N. Lo, Estella P.S. Tong, Bonnie W.Y. Wong, Andrew L.T. Chan, Vincent C.T. Mok, Timothy C.Y. Kwok, Kin Y. Mok, John Hardy, Henrik Zetterberg, Amy K.Y. Fu, Nancy Y. Ip. Large‐scale plasma proteomic profiling identifies a high‐performance biomarker panel for Alzheimer’s disease screening and staging.

    8. Nature Aging. 2021. Jiansong Fang, Pengyue Zhang, Yadi Zhou, Chien-Wei Chiang, Juan Tan, Yuan Hou, Shaun Stauffer, Lang Li, Andrew A. Pieper, Jeffrey Cummings, Feixiong Cheng. Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease.

    9. Molecular Psychiatry. 2021. Naoto Watamura, Naomasa Kakiya, Per Nilsson, Satoshi Tsubuki, Naoko Kamano, Mika Takahashi, Shoko Hashimoto, Hiroki Sasaguri, Takashi Saito, Takaomi C. Saido. Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-KATP channel pathway.

    10. Frontiers in Aging Neuroscience. 2021. Samantha L. Gardener, Stephanie R. Rainey-Smith, Victor L. Villemagne, Jurgen Fripp, Vincent Doré, Pierrick Bourgeat, Kevin Taddei, Christopher Fowler, Colin L. Masters, Paul Maruff, Christopher C. Rowe, David Ames, Ralph N. Martins. Higher Coffee Consumption Is Associated With Slower Cognitive Decline and Less Cerebral Aβ-Amyloid Accumulation Over 126 Months: Data From the Australian Imaging, Biomarkers, and Lifestyle Study.

    11. PLOS Medicine. 2021. Yuan Zhang, Hongxi Yang, Shu Li, Wei-dong Li, Yaogang Wang. Consumption of coffee and tea and risk of developing stroke, dementia, and poststroke dementia: A cohort study in the UK Biobank.

    12. Rohan Jagirdar, Chia-Hsuan Fu, Jin Park, Brian F. Corbett, Frederik M. Seibt, Michael Beierlein, Jeannie Chin. Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aβ accumulation in mice.

    13. Science Advances. 2021. Hideaki Sato, Yuhei Takado, Sakiko Toyoda, Masako Tsukamoto-Yasui, Keiichiro Minatohara, Hiroyuki Takuwa, Takuya Urushihata, Manami Takahashi, Masafumi Shimojo, Maiko Ono, Jun Maeda, Asumi Orihara, Naruhiko Sahara, Ichio Aoki, Sachise Karakawa, Muneki Isokawa, Noriko Kawasaki, Mika Kawasaki, Satoko Ueno, Mayuka Kanda, Mai Nishimura, Katsuya Suzuki, Akira Mitsui, Kenji Nagao, Akihiko Kitamura, Makoto Higuchi. Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model.

    14. Molecular Nutrition & Food Research. 2021. Raúl González‐Domínguez, Pol Castellano‐Escuder, Francisco Carmona, Sophie Lefèvre‐Arbogast, Dorrain Y. Low, Andrea Du Preez, Silvie R. Ruigrok, Claudine Manach, Mireia Urpi‐Sarda, Aniko Korosi, Paul J. Lucassen, Ludwig Aigner, Mercè Pallàs, Sandrine Thuret, Cécilia Samieri, Alex Sánchez‐Pla, Cristina Andres‐Lacueva. Food and Microbiota Metabolites Associate with Cognitive Decline in Older Subjects: A 12‐Year Prospective Study.

    15. Frontiers in Aging Neuroscience. 2021. Atefeh Razazan, Prashantha Karunakar, Sidharth P. Mishra, Shailesh Sharma, Brandi Miller, Shalini Jain and Hariom Yadav. Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis.

    16. International Journal of Molecular Sciences. 2021. Jing Xu, Ichiro Kawahata, Hisanao Izumi, Kohji Fukunaga. T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model.

    17. Cell. 2021. Mathieu Bourdenx, Adrián Martín-Segura, Aurora Scrivo, Jose A. Rodriguez-Navarro, Susmita Kaushik, Inmaculada Tasset, Antonio Diaz, Nadia J. Storm, Qisheng Xin, Yves R. Juste, Erica Stevenson, Enrique Luengo, Cristina C. Clement, Se Joon Choi, Nevan J. Krogan, Eugene V. Mosharov, Laura Santambrogio, Fiona Grueninger, Ludovic Collin, Danielle L. Swaney, David Sulzer, Evripidis Gavathiotis, Ana Maria Cuervo. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.