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The focus on the amyloid cascade hypothesis in Alzheimer's research has led to the development of drugs targeting amyloid plaques. However, recent evidence suggests that the relationship between amyloid beta and Alzheimer's is more complex than previously thought. A study conducted by researchers at the University of Cincinnati found that higher levels of soluble amyloid beta-42 were associated with lower cognitive decline, challenging the prevailing hypothesis. Another study suggests that the diabetes drug metformin may reduce the risk of Alzheimer's by increasing amyloid beta-42 levels. The FDA-approved drug licanamab, which targets amyloid plaques, has been found to worsen cognitive decline in some patients. These findings indicate the need for fresh ideas and new avenues of research in the field of Alzheimer's. Given that the imagination behind research and funding of Alzheimer's disease has largely focused on the amyloid cascade hypothesis, it's no wonder that the focus has been on developing drugs that target these amyloid plaques. However, a growing body of evidence suggests that the relationship between amyloid beta and Alzheimer's is more complex than initially thought. In a study published last month in the journal Brain, researchers under Dr. Alberta Este from the University of Cincinnati conducted a meta-analysis on published papers concerning monoclonal antibody therapies for the treatment of Alzheimer's. From 24 clinical trials encompassing over 25,000 Alzheimer's patients, their literature review investigated the impact these anti-amyloid antibody treatments had on both insoluble amyloid plaques and soluble amyloid beta-42 levels in the cerebral spinal fluid. Their findings have created a whirlwind in the Alzheimer's research community by challenging the prevailing amyloid cascade hypothesis, suggesting that soluble alpha-beta-42, suggesting that soluble amyloid beta-42 may play a more significant role in cognitive function than previously recognized. Quote, all stories have two sides, even the one we have told ourselves about how anti-amyloid treatments work, by lowering amyloid, as they said. In fact, they also raise levels of amyloid beta-42. If this is unintended, it is why there may be a benefit. Our study shows that we can predict changes in cognitive outcomes in anti-amyloid trials at least as well by the increases in amyloid beta-42 as by the decreases in amyloid. That quote was from Dr. Alberto J. Este of the University of Cincinnati study. The UC study found a striking correlation in the data. Increased amyloid beta-42 levels were associated with lower cognitive decline, while those that decreased amyloid beta-42 levels were linked to faster cognitive decline, regardless of the status of insoluble amyloid beta plaques in the brain. This suggests that soluble amyloid beta-42 may actually have a protective effect in the brain when it is not at or above normal levels. Quote, most of us will accrue amyloid plaques in our brains as we age, and yet very few of us with plaques go on to develop dementia. Dr. Alberto J. Este, professor of urology, UC College of Medicine. To further understand the implications of the UC study, let's explore three other research articles that provide support for this new perspective on amyloid beta and the need for fresh ideas in a field that has been focused on one hypothesis for over three decades. The first supportive article, also published in the journal Brain, focuses on metformin, a widely prescribed diabetes drug that has also become a pop cultural phenomenon due to a drug of its same class being used widely for weight loss, ozempic. Researchers Timothy Daly and Bruno Mbimbo reviewed evidence suggesting that metformin may reduce the risk of Alzheimer's disease, and they proposed a fascinating mechanism beyond metformin's traditional effect on glucose metabolism. They suggested metformin's ability to increase serum amyloid beta-42 levels. The researchers furthered their argument by citing a large population-based study that demonstrated a protective effect of metformin when given in high doses on the onset of Alzheimer's disease in those over 65 years old with type 2 diabetes, suggesting that metformin may delay or prevent Alzheimer's disease development. Additionally, they pointed to a study from the Alzheimer's disease neuroimaging initiative, which found that patients with mild cognitive impairment, MCI, who were taking metformin had higher levels of amyloid beta-42 in their cerebral spinal fluid. To prove metformin's amyloid beta-raising bona fides, Daly and Mbimbo highlighted laboratory studies demonstrating that metformin can directly increase amyloid beta-42 production in both cell cultures and animal models. This research, when viewed in conjunction with the UC study, strengthens the argument that increasing soluble amyloid beta-42 levels may be a promising avenue for preventing or slowing the progression of Alzheimer's disease. Furthermore, Daly has argued that metformin and monoclonal antibody treatments being the only two drugs shown to increase CSF amyloid beta-42 at this time, metformin is a much safer alternative than monoclonal antibodies, which are quickly gaining a reputation for severe adverse effects that have already been deadly for some patients. The authors highlight an upcoming study. Metformin in Alzheimer's dementia prevention, which could prove that the UC team was correct in thinking the increase of soluble amyloid beta-42 in serum was responsible for the successful anti-amyloid beta monoclonal antibody studies. Daly highlights that this is because the monoclonal antibodies are sought to increase serum amyloid beta-42 by releasing it from the brain plaques, whereas metformin is sought to increase amyloid beta-42 by breaking down amyloid beta precursor proteins. Demonstrating the amyloid beta-42 mediated efficacy of metformin in the early stages of Alzheimer's disease could therefore add impetus to a growing body of literature on the potential therapeutic value of increasing soluble amyloid beta-42 concentrations in patients with Alzheimer's disease. Demonstrating the amyloid beta-42 mediated efficacy of metformin in the early stages of Alzheimer's disease could therefore add impetus to a growing body of literature on the potential therapeutic value of increasing soluble amyloid beta-42 concentrations in patients with Alzheimer's disease. Timothy Daly and Bruno Mzienbo. The second article I'd like to offer as support for the UC study was published in Advances in Clinical Experimental Medicine and offers a critical analysis of the clinical trial data for Lecanat and offers a critical analysis of the clinical trial data for Lecanamab, a recently FDA-approved anti-amyloid beta monoclonal antibody drug that targets the removal of amyloid plaques in the brain. The author, Dr. Maddy Kurkainen, cautions against oversimplifying the results of the Lecanamab trial. In this article, Dr. Mark Kulkurkainen's analysis goes beyond initial reports of the relative success of this treatment compared to past failed trials of monoclonal antibodies for Alzheimer's by revealing that Lecanamab actually worsens cognitive decline in a subset of trial participants. The first being patients whose genes contain two copies of the APOE4 gene, a known genetic risk factor for Alzheimer's. The second group with less than stellar results was women, having very minimal improvements in cognition that were barely statistically significant. Dr. Kurkainen goes so far as to chastise the authors of the Lecanamab trials for not highlighting these results in favor of heralding a success story for the amyloid hypothesis. Why were these data not disclosed, not even discussed within the paper? Indeed, the words man and woman or male and female were not used in the paper, not even once. These negative results regarding Lecanamab's therapeutic value make me wonder if the approval of Lecanamab was the worst decision of the FDA up until now after the approval of aducanamab on June 7th, 2021, Dr. Marku Kurkainen. This article supports the UC study indirectly by pointing out that the research community for neurodegenerative disease needs to move on from its primary focus on the amyloid cascade hypothesis and to not shut out other potential avenues of research due to the sunk cost fallacy as it applies to the billions spent on amyloid cascade research. Researchers in the UC study agree that we need a sea change in how we see the disease, asking us to accept that the opposite of what we think we know might be true. Researchers in the University of Cincinnati study agree that we need a sea change in how we study Alzheimer's disease. They ask us to accept that the opposite of what we think we know might turn out to be true. Quote, you can't cheat to cure a disease, biology doesn't care, Dr. Matthew Schrag. The final article I'd like to share in support of the Cincinnati team's groundbreaking research was featured in the New York Times as an editorial written by Charles Pilar, an investigative journalist for Science Magazine and writer of an upcoming book detailing rampant fraud taking place in Alzheimer's research. Mr. Pilar makes the case that science and humanity at large have been led astray by the same hypothesis that our UC cohort calls into question. Mr. Pilar details how even though anti-amyloid drugs have failed time and time again since the hypothesis became popular in the 90s, this was revived in the hypothesis by... Mr. Pilar makes the case that science and humanity at large have been led astray by the same hypothesis that our University of Cincinnati cohort calls into question. Mr. Pilar details how even though anti-amyloid drugs have failed time and time again since the hypothesis became popular in the late 1980s, it was revived by a study in 2006. This was an animal experiment study published in the journal Nature which identified for the first time a specific type of protein, beta-amyloid 42, as the direct causal agent in Alzheimer's after the authors claimed to have isolated the substance, injected it into the brains of mice, and detailed how the mice rapidly lost their cognitive ability. Scientists hailed this study as a breakthrough. The NIH renewed its fervor for the once-failed hypothesis by throwing the majority of its Alzheimer's budget at the amyloid cascade, and the study became one of the most cited papers in Alzheimer's research, with 2,300 academic articles citing the 2006 study, making it the fifth most cited in the Alzheimer's field. Mr. Pilar points out that this pivotal study has been the background of the drug luteinamab discussed earlier, which has been hailed by proponents of the amyloid theory as the final proof of its accuracy. The only problem here, as Pilar lets us know, is that it has been fully retracted from the journal Nature from its inception. The only problem here with this 2006 study is that it has been fully retracted from the journal Nature for manipulated images and data fraud after Dr. Matthew Schrag was tipped off by web sleuths that there may be inconsistencies in he began his research. This retraction alone should allow us all to consider the UC research team's call to action for examining novel research topics in the field, but for the unconvinced there is more. Within days of the Nature retraction, employees of Pisada Scientists and a CUNY professor were both indicted for collaborating to produce 34 articles containing fabricated research for their newest amyloid-based drug, simulfam, which is already in stage 3 trials. I believe this source is the strongest evidence for the overarching ideals behind the University of Cincinnati research team's mission to change the paradigm in Alzheimer's research to encourage creative approaches once again. Quote, there is an entrenched echo chamber that involves a lot of big names, Dr. Schrag says. It's time for the field to move on, Dr. Matthew Schrag. The University of Cincinnati findings are a sea change from currently accepted theory that Alzheimer's disease is caused by an accumulation of amyloid beta plaques. The authors are asking us to consider that the complete opposite of this prevailing belief may be true in that increased levels of amyloid beta result in less cognitive decline. Karen D. Sullivan, Ph.D., ABPP, a board-certified neuropsychologist and Reed Healthcare Transformation Fellow. The search for effective treatments for Alzheimer's disease continues, and these studies represent an important step forward. By challenging conventional thinking and exploring new avenues, scientists are paving the way for a deeper understanding of this complex disease and, ultimately, for the development of therapies that offer hope for those affected by Alzheimer's. That hope extends personally to myself and my family. Three out of my four grandparents struggled with Alzheimer's in their 80s, and it took all of our extended family to provide them the round-the-clock care they needed and deserved. My paternal grandfather, the first of my grandparents to have mild cognitive impairment symptoms, was first started on cholinesterase inhibitors, which did give him a few more months of clear cognition, but did not slow down the disease's progression to Alzheimer's. We felt very lucky that he was able to take part in an early anti-amyloid immunotherapy trial not dissimilar from Leucanumab, which we discussed today. Not so soon after starting this drug trial, he became withdrawn at family gatherings, and the joyful man we knew gave way to one who had a deep anger lurking just under the surface. He had a severe weakness and could not walk without assistance. A routine checkup on the progress of his medication showed severe cerebral edema, and my grandfather was rushed into surgery for an intracranial scent to be placed. The scent gave us back our beloved grandfather for another year, and I still wonder if the immunotherapy drug that he had tried took more time from him than he gained from the treatment. When reading medical news today at the beginning of the semester, I came across the work of the Cincinnati research team in an article titled, New Study Challenges Amyloid Beta Theory on Cause for Alzheimer's Disease. To say that I was intrigued would be laughable as an oversimplification. Reading more about the image and data manipulation that has occurred to sure up the amyloid cascade hypothesis, I am proud to know that the University of Cincinnati is working to break the field's reliance on this outdated theory.