Retiring the Amyloid Cascade Hypothesis as a Cause of Alzheimer’s
August 31, 2017
When you consider the decades-long track record of dead-end Alzheimer’s disease research, it's reasonable to ask: What drives this research? The amyloid cascade hypothesis has been foundational for Alzheimer’s disease research and drug development since its description based on mouse experiments by Hardy and Allsop in 1991 and a noteworthy Science update in 2002. Postmortem exams of Alzheimer’s disease patients in the 1970s and 1980s had characterized accumulations of amyloid plaques that soon became a hallmark of the disease. As often happens, researchers took this clinical finding back to the lab, and a long history of Alzheimer’s disease animal research (predominantly in mice and rats) ensued.
Amyloid is a protein found in the brain. The amyloid cascade hypothesis states that the cause for Alzheimer’s disease is one or more mutations which cause the protein to be cleaved, producing a sticky protein fragment called beta-amyloid. This protein fragment forms plaques in the brain that begin the "cascade" leading to the formation of neurofibrillary tangles. The beta-amyloid plaques and neurofibrillary tangles cause inflammation and destruction of neurons to produce the clinical signs and symptoms of Alzheimer’s disease.
Widespread acceptance of this hypothesis has dominated the directions of basic science and clinical research and influenced funding agencies such as the National Institutes of Health, journal editors, peer reviewers, and pharmaceutical companies. With so much time and money invested in the animal-derived model of Alzheimer’s disease's cause, it has been difficult for researchers with novel approaches to obtain support for their work. Alzheimer’s disease scientists, funding agencies, patient advocacy groups, and Big Pharma have bet the ranch on the amyloid cascade hypothesis as the key to tracking and treating Alzheimer’s disease.
However, abundant information has been discovered casting doubt on the amyloid cascade hypothesis. Among contrary information is the finding that a meaningful percentage of young adult and older persons without dementia have substantial beta-amyloid plaque deposition demonstrated on brain imaging and postmortem studies. Dr. Lon Schneider of the University of Southern California Keck School of Medicine has stated: "There are people who die with a head full of amyloid and have no cognitive impairment whatsoever." Conversely, beta-amyloid plaques may be absent or minimally present in clinically diagnosed Alzheimer’s disease patients. A recent report demonstrates that tau oligomers, produced after beta-amyloid deposition, also are present in the sera of unaffected people of the same age as well as Alzheimer’s disease patients, and it has been reported (here and here) that some degree of tau pathology is ubiquitous in postmortem human brains, including unaffected and young persons.
Hundreds of drugs developed on the basis of the amyloid cascade hypothesis have been tested in Alzheimer’s disease clinical trials, and the overall failure rate for 244 drugs in 413 trials just from 2002-2012 is reported to be 99.6 percent. Only a single drug was approved from these trials (memantine in 2003). An analysis of subsequent Alzheimer’s disease clinical drug trials reported from Jan. 1, 2004, (after memantine approval) through July 19, 2017, reveals 1,273 completed or closed trials and no approved drugs. Only four drugs are approved overall for treating various stages of Alzheimer’s disease, and they offer minimal if any temporary symptomatic benefit to a minority of patients, with no effect on long-term prognosis or survival. No disease-modifying drugs have been developed based on the science and pharmacology of the amyloid cascade hypothesis.
Since some drugs have successfully removed brain beta-amyloid plaques without producing improvement in cognition and other symptoms, and without improving clinical course or mortality, it has been proposed that beta-amyloid plaques may not be causative for Alzheimer’s disease. Tau pathology not only is triggered by beta-amyloid plaques and disrupts brain intracellular functions, but also appears to progress even after removal of beta-amyloid plaques, suggesting that therapies targeting beta-amyloid cannot succeed in controlling Alzheimer’s disease. Some recent research has focused on a possible role for tau proteins rather than beta-amyloid plaques, but the only completed tau-targeting phase 3 drug trial (a tau protein aggregation inhibitor known as LMTX, LMTM, or TRx0237) failed to show benefits.
Some researchers believe that the timing of beta-amyloid-targeted therapies may be key: once substantial beta-amyloid plaque has formed and tau pathology has occurred, it may be too late to reverse the pathological consequences. Clinical trials are thus employing earlier detection and intervention for Alzheimer’s disease, even before symptoms occur, often by using biomarkers to identify at-risk persons.
Earlier intervention is derived logically from the failure of later clinical intervention, but its value is debatable for at least three reasons. First, the biomarkers indicating risk for Alzheimer’s disease are not yet sufficiently accurate to exclude from clinical trials those who would never develop Alzheimer’s disease or even mild cognitive impairment. Second, fewer than half of those with mild cognitive impairment will develop Alzheimer’s disease, making even this later indicator of limited utility and suggesting that earlier biomarkers may have low predictive value (here and here). Third, this approach does not directly address the failure of animal and other basic science research to identify disease-modifying therapies, though it is postulated that some failed therapies may be effective if applied earlier.
So the validity of the amyloid cascade hypothesis remains unknown but appears tenuous. Its demise would largely invalidate decades of basic science, clinical, and pharmaceutical work. Outcomes to date do not support the validity of the amyloid cascade hypothesis, and if current and pending early-stage and presymptomatic beta-amyloid-targeted studies fail to impact outcomes, it must be presumed to be incorrect.
That would be another heavy blow against the reliability of animal research, in this case for a fatal disease with increasing prevalence. It is self-evident that the first step in treating disease is to determine the cause(s). We have not demonstrably done this for Alzheimer’s disease, arguably because animal research has been unable to accomplish the task despite more than three decades of effort.
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