August 23, 2022
The Controversial Aβ: ReCODE to the Rescue
By Ram Rao, Ph.D., Principal Research Scientist for Apollo Health
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 will require 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 ReCODE protocol 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 were, in fact, the causative agent of plaque formation. The plaque has a dense core of protein aggregates and is surrounded by damaged neighboring neurons. Activated astrocytes and microglia, which are part of 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 “cascadehypothesis” 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. This idea got overwhelming support from families across the world (in Sweden, Dutch, Colombia, and more) that harbored mutations in the parent APP that led to accelerated Aβ accumulation triggering early development of AD symptoms.
With major organizations like the National Institutes of Health and the Alzheimer’s Association providing millions of dollars in funds to target Aβ and find a cure for AD, 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. All forms of “treat-the-amyloid-associated-symptoms” approaches were investigated as treatment targets, including 1) the enzymes that cleave APP protein to give rise to Aβ, 2) small drug molecules that would slow down Aβ aggregation or accelerate its clearance, and 3) antibodies against various forms of Aβ itself to suppress its toxicity and cause it to be cleared by the immune system. Every single one of these interventions has failed miserably in clinical trials.
Last year, the FDA approved Aduhelm despite poor clinical trial data. Aduhelm, the formal name for Aducanumab, was designed to clear the accumulation of Aβ protein from the brain. However, clinical trials of the drug failed to show any significant reversal of the actual symptoms of AD. The design and mechanistic action of Aduhelm and other 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 now Aducanumab — reduced the Aβ protein but did not improve cognition and memory, leaving more than five million Americans who suffer from AD with fewer options. In short, Aducanumab and other failed drugs are more of an amyloid-modifying drug and less of an AD-reversing drug. The thought of making billions of dollars with a drug that reduces amyloid without treating AD has kept the entire Alzheimer’s field going in the wrong direction.
Despite the failures of anti-amyloid therapies, researchers, clinicians, and biotech companies are still focused on Aβ strategies. Their reasoning — while Aβ is the key molecule to go after, 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 the disease might have manifested in several different but undetected ways, and the wrong kind of patients got enrolled in the trials, 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 this last 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 Aβ, insoluble Aβ, Aβ oligomers, Aβ protofibrils, and Aβ fibrils. Research scientists who discover 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 many papers on Aβ*56 and its role in memory and cognition, and several of the papers have been well cited by other researchers. While these findings made big news generating tremendous enthusiasm about a potential link between Aβ*56 and cognitive decline, 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 evidence of tampering — the researcher “created Aβ*56” by manipulating data images in multiple manuscripts. While investigations are still ongoing, most researchers agree that this entire controversy has put the credibility of AD research in poor light with plenty of blame game between co-authors, university and departmental staff, other scientists that shared materials with the researcher, as well as reviewers and journal editorial staff members.
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, in addition to the Aβ protein, the gut microbiome, inflammatory mediators, apolipoproteins, vitamins, minerals, hormones, neurotrophic molecules, neurotransmitters, and a host of other potential targets. Thus, it is clear that for a successful treatment, a mono-therapeutic drug strategy is not optimal; instead, 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 feasible and potentially more effective for AD treatment.
While the entire saga around the controversial researcher may create mistrust among the public in AD research, more and more people trust the work that we are doing at Apollo Health as it has fundamentally changed the way we view and approach cognitive health. Our work has gone beyond Aβ — the villain in all of the controversial reports 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 studies1 and the proof-of-concept clinical trial2 that has now paved the way for a larger-randomized-controlled trial. The approach we have pioneered with the ReCODE program is the future of medicine: identifying the underlying contributors to cognitive decline and targeting those specifically, rather than attempting to treat with an ineffective mono-therapeutic unrelated to the cause of the memory and cognitive decline.