Everything old is new again. It was just a few years ago that a promising drug to treat Alzheimer’s disease was stopped in its tracks owing to phase III clinical trials being halted due to subjects in the treatment group faring so much worse than those in the placebo group. And now, another drug on which high hopes rested has proven to be a disappointment. The drug, called solanezumab, was also intended to reduce aggregation of the beta-amyloid (Aβ) proteins long believed to be causal agents in disease etiology and progression. This is a blow, of course, to doctors, Alzheimer’s patients, and loved ones and caregivers of those afflicted with dementia. Because there have been essentially no pharmaceutical interventions that effectively halt, delay, or reverse disease progression, each new drug that’s developed is lauded as a potential breakthrough. A game changer. A miracle drug. And yet, these claims have failed time and again to live up to expectations.
This comes as no surprise to progressive and forward-thinking Alzheimer’s researchers. It is virtually impossible to come across a published paper on Alzheimer’s that doesn’t take for granted the causal role of Aβ plaques. It is often presented as established fact that the formation of these plaques is a triggering event in the condition. But if this proves not to be the case—and increasing evidence suggests just this—then the amyloid hypothesis will simply be the newest addition to the list of concepts that medical science once believed and held dear, but which have been disproven over time. (It will be in good company if it joins the ranks of outdated and false notions, such as saturated fats being harmful and “clogging the arteries,” and low sodium diets being beneficial for everyone.)
This latest failure of a drug designed to target the amyloid plaques lends more weight to the increasing body of evidence that suggests amyloid proteins are not primary causal agents in Alzheimer’s. While the aggregation of these protein fragments into insoluble plaques no doubt interferes with synaptic transmission, in many cases, significant plaque deposition does not occur until late in disease progression. Moreover, there are Alzheimer’s patients who do not exhibit significant plaque burden, and there are individuals who do have plaque deposition but are not suffering from dementia. Groups of people with normal cognition and groups with Alzheimer’s both consist of individuals with and without significant amyloid deposition. This uncomfortable fact is downplayed and sometimes even ignored in the medical literature, as these individuals “cannot be explained and do not fit the paradigm.”
When evidence does not fit the paradigm, it should not be swept aside and ignored. It should cause a fundamental reevaluation of the paradigm and drive researchers to question whether the paradigm is even valid. (French paradox, anyone? Spanish paradox? Greek paradox? The fact that these cultures follow higher fat diets and have lower rates of obesity and heart disease doesn’t make this a “paradox.” It means that higher fat diets do not, by themselves, directly cause obesity and heart disease.) Thankfully, this is happening, albeit slowly, in the Alzheimer’s community.
At the very least, the amyloid hypothesis should be revisited and revised, in order “to reconcile data from recent drug failures.” There may even be a protective role for amyloid proteins. According to Dale Bredesen, MD, who has designed a multi-pronged diet and lifestyle protocol that has been shown to reverse Alzheimer’s and its precursor, mild cognitive impairment (MCI), in a small but extremely promising study, “The production of the amyloid is a protective response. […] The idea of just getting rid of the amyloid without understanding why it’s there actually makes very little biological sense.” Other researchers agree: they “propose that Aβ is a key regulator of brain homeostasis. During AD, while Aβ accumulation may occur in the long term in parallel with disease progression, it does not contribute to primary pathogenesis. This view predicts that amyloid-centric therapies will continue to fail, and that progress in developing successful alternative therapies for AD will be slow until closer attention is paid to understanding the physiological function of Aβ and its precursor protein.”
The primary driving factor in Alzheimer’s—a reduction in the capacity of neurons in specific regions of the brain to harness energy from glucose—occurs long before plaque deposition. Moreover, “the formation of Aβ may actually be an element in the brain’s defense against oxidative stress […] Oxidative stress may then provoke the protective release of Aβ.”
If amyloid proteins are, in fact, a protective mechanism, then it makes sense that drugs intended to prevent the formation of these proteins have either had no impact on disease progression, or, as the case has been, have actually caused the disease to worsen. The amyloid hypothesis has many shortcomings and fails to account for many of the metabolic and physiologic abnormalities in AD and MCI. Continuing to funnel research dollars toward this failed trajectory will only delay research into avenues that are far more promising, in particular, metabolic therapies involving ketone-based brain fuel metabolism. Researchers are slowly beginning to realize this, and some are shifting from the amyloid focus to a mitochondrial hypothesis, wherein mitochondrial dysfunction—and the resulting disruption of cellular energy production—is believed to be the driving factor in cognitive decline.
Amy Berger, MS, CNS, NTP
Author of The Alzheimer’s Antidote
Related DFH Products:
Sponsored Blog
I am eternally grateful to our sponsors who, by blogging, podcasting, and advertising with us, enable me and my team to devote energy and time to writing and publication. All the companies who sponsor us are companies that I trust for myself and my patients and use regularly in my clinical practice. Please check out their websites! – Dr. KF
Hi Dr. Fitzgerald, i have spoken to Dr.Thomas J. Lewis ,PHD he and Dr. Clement L. Trempe they wrote “The end of Alzheimers” a great book allDr.s should read as well as people concerned with mental health and over all wellness. Eric