Precipitous fall of star-Aβ
Most of you may be aware and shocked by the latest controversy in the Alzheimer’s field involving allegations against a prominent researcher at the University of Minnesota. The researcher is believed to have manipulated data images in multiple papers some of which were published in high profile journals like Nature and J. Neuroscience. The altered images pertained to a form of amyloid called Aβ*56 (amyloid-beta star 56) believed to be associated with cognitive decline. To explain this controversy, let me to provide some background and history of Alzheimer's disease (AD) that would enable us to clearly understand the current outcry and also appreciate that the successful work that we are doing is not affected by this controversy in any way.
It all started in the early 1900s when German psychiatrist and neuropathologist Alois Alzheimer identified plaques and?neurofibrillary tangles in the brains of people who had died with memory loss and dementia. His neuropathological observations served as a harbinger of what later became known as?Alzheimer's disease (AD). In the mid-1980s, the principal protein in the plaques was conclusively identified as amyloid-beta (also known as Aβ), a 36 to 42 amino acid short peptide that had a strong tendency to aggregate and clump into various forms. In the early 1990s, several laboratories identified the parent amyloid precursor protein (APP) from which Aβ was generated. It was shown that excess levels of misfolded Aβ triggered plaque formation. The plaque has a dense core of protein aggregates and is surrounded by damaged neighboring neurons. Activated astrocytes and microglia that constitute the immune response are present in the plaque as well, suggesting abnormal tissue degeneration and failure of the brain’s repair mechanisms. Thus was born the “cascade hypothesis” or the “amyloid hypothesis” as the cause of Alzheimer and for the last thirty years this hypothesis became the hot and dominating idea in the field. Thus, researchers, clinicians and hundreds of biotech companies spent a fortune (in terms of money, time and effort) trying to turn the amyloid hypothesis into a treatment for AD.?However, every single drug of choice has failed miserably in clinical trials.
?The design and mechanistic action of all the failed drugs for AD are based on a misconception that removing Aβ would ameliorate AD symptoms. Unfortunately, this line of thinking is completely incorrect as the various amyloid removing drugs — including donanemab, solanezumab, bapineuzumab, and the recently approved Aducanumab reduced the Aβ protein but did not improve cognition and memory. In short, Aducanumab and other failed drugs are more of an amyloid-modifying drug and less of an AD-reversing drug. Despite the failures of anti-amyloid therapies, researchers, clinicians and biotech companies are still focused on Aβ strategies. Their reasoning—perhaps the people enrolled in the failed clinical trials were in the late stage of AD and patients needed to be treated much earlier, OR maybe the different forms and species of Aβ were not being targeted correctly. The latest controversy involving the prominent researcher at the University of Minnesota stems from the latter reasoning.?
Inside a cell, short misfolded proteins like Aβ have a tendency to clump and bind to other cellular targets and form all kinds of aggregates. Thus, thousands of research papers have described the existence of various forms of Aβ protein in animal models of AD including among others soluble amyloid, insoluble amyloid, Aβ oligomers, Aβ protofibrils and Aβ fibrils. Research scientists who identify the various Aβ forms link their “discovered forms” of Aβ to AD-associated neurodegeneration. One such discovery involved the controversial researcher who declared that a novel form of Aβ called Aβ*56 that he identified is associated with memory loss and cognitive decline. The researcher continued to publish several papers linking Aβ*56 to memory and cognition and several of the papers have been well cited by other researchers. While these findings made big news generating tremendous enthusiasm and numerous grants and funds from several sources, the excitement as we know it now was short-lived. Numerous investigations by independent analysts have questioned the existence and validity of Aβ*56 by revealing evidences of tampering — the researcher “created Aβ*56” by manipulating data images in multiple manuscripts. While investigations are still ongoing, most researchers agree that this controversy has put the credibility of AD research in poor light.
Undoubtedly, the entire approach taken to target Aβ protein and reverse AD is not an optimal one — standard of care medicine involving a single drug may work well for illnesses like malaria or TB, but not for complex chronic conditions like AD. And the reason is clear: genetic and biochemical research studies have revealed an extensive network of molecular interactions involved in AD development. These include the gut microbiome, inflammatory mediators, apolipoproteins, vitamins, minerals, hormones, neurotrophic molecules, neurotransmitters, and a host of other potential targets. Thus, the most pragmatic approach would involve addressing these multiple targets underlying AD pathophysiology simultaneously; in other words, a network-based, multi-therapeutic approach may be more effective for AD treatment.
While the entire saga around the controversial researcher may create mistrust among the public in AD research, amidst this thorny issue, a more flowery and trustworthy treatment paradigm is emerging — in the form of a programmatic approach. The work that we are doing at Apollo Health has gone beyond Aβ and has clearly demonstrated that reversal of cognitive decline is possible by addressing not Aβ but other contributors to cognitive decline. Our results have been confirmed by observational studies (1) and the proof-of-concept clinical trial (2) that has now paved the way for a larger-randomized-controlled trial. The approach we have pioneered with the ReCODE (Reversal of Cognitive Decline) program is the future of medicine: identifying the underlying contributors to cognitive decline and targeting those specifically, rather than attempting to treat a single molecule with an ineffective mono-therapeutic unrelated to the cause of the memory and cognitive decline.?
Program Director
2 年Excellent article, Ram!
Carol P. Prentice. Conscious LifeStyle | Conscious Dying
2 年Thank you, Ram, for this article. My sister was just diagnosed with mild cognitive impairment at the age of 65, so I have been doing a lot of research in this area. I feel that there is a lot of misinformation out there as well as giving people false hope with the AZ drugs that are being prescribed. As we know from āyurveda, diet, lifestyle, sleep, exercise, and some herbs are key to helping prevent aging as well as maintaining a healthy brain. The ReCode program that Apollo Health and Dr. Bredesen have put together seems like a very smart way to go. Are you finding people able to make that commitment?