A new drug has been approved for Alzheimer’s disease amid controversy.
The FDA recently approved the drug aducanumab, or Aduhelm, to treat Alzheimer’s disease, but studies indicate that Aduhelm reduces levels of amyloid, although that may not ultimately reduce cognitive decline.
When German psychiatrist Alois Alzheimer made the post-mortem discovery of amyloid plaques and neurofibrillary tangles in the early 1900s, he birthed the discovery of a cruel and insidious disorder. Today, nearly 6 million people in the United States are diagnosed with Alzheimer’s disease, a disorder characterized by short-term memory loss followed by a progressive decline in social behavior, language, and reasoning (Hebert et al., 2003). Ultimately, the disease is fatal.
For the first time in nearly 20 years, the FDA has approved a new drug, aducanumab (brand name Aduhelm), for the treatment of Alzheimer’s disease. Whereas other approved drugs for the treatment of Alzheimer’s disease, such as cholinesterase inhibitors, are meant to minimize the cognitive symptoms of Alzheimer’s disease, Aduhelm is the first drug that purports to attack the disease process itself.
While the Aduhelm’s approval was heralded as a beacon of hope for many, it was not received without controversy. Aduhelm was approved via the FDA’s accelerated approval program, whereby certain drugs may gain approval despite uncertainty about the extent of their effectiveness.
This program is typically utilized when there are significant unmet needs for serious disorders.
Essentially, the potential benefits of Aduhelm were believed to outweigh the potential risks. The potential risks, however, are quite serious. About 40% of the patients across two of the drug’s clinical trials developed swelling in the brain and another ~17% of patients had small brain bleeds (Alexander, Emerson, & Kesselheim, 2021).
Despite significant doubts that Aduhelm is indeed effective for slowing cognitive decline, it was approved based on its mechanism of action.
Specifically, the evidence demonstrates that Aduhelm substantially reduces levels of amyloid, the protein that clumps into plaques and is the biomarker of the Alzheimer’s disease process; the very plaques noted by Alois Alzheimer himself in 1906. Thus, its approval is predicated on the amyloid hypothesis, which suggests that the buildup of amyloid is responsible for the pathogenesis of Alzheimer’s disease. However, there is yet to be significant evidential support of the amyloid hypothesis.
Insights from Schizophrenia
The schizophrenia literature, in fact, would argue against the amyloid hypothesis. New evidence via diffusion tensor imaging (DTI) continues to blur the lines between schizophrenia and dementia.
Both diagnostic groups, for example, are marked by cognitive deficits. Alois Alzheimer himself was both friends and colleagues with Emil Kraeplin, the founder of the “original schizophrenia,” then termed: “dementia praecox.” Kraeplin was the first to remark on what we now know today: that schizophrenia is marked as much by cognitive deficits as it is by psychosis, and that it likely has more in common with various dementias than previously thought.
How does this relate to amyloid plaques? While the type and severity of cognitive deficits are similar across schizophrenia and various types of dementia, the level of amyloid protein is not. Individuals with schizophrenia have cognitive deficits despite normal levels of amyloid, thus suggesting other networks and tracts are likely responsible for cognitive decline (Chung et al., 2016).
The false equivalence suggested by Aduhelm may prove to be problematic. Reducing amyloid is not the same as reducing cognitive deficits. While it is still possible that amyloid plaques play, at the very least, a mediating role in the manifestation of cognitive deficits, they are not the whole story. Thus, the benefits of Aduhelm remain to be seen.
Source: Brielle A. Marino, Psy.D. / Psychology Today.
Alexander, G. C., Emerson, S., & Kesselheim, A. S. (2021). Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA, 325(17), 1717-1718.
Chung, J. K., Nakajima, S., Plitman, E., Iwata, Y., Uy, D., Gerretsen, P., … & Graff-Guerrero, A. (2016). Β-Amyloid Burden is Not Associated with Cognitive Impairment in Schizophrenia: A Systematic Review. The American Journal of Geriatric Psychiatry, 24(10), 923-939.
Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A., & Evans, D. A. (2003). Alzheimer disease in the US population: prevalence estimates using the 2000 census. Archives of neurology, 60(8), 1119-1122.
Religa, D., Laudon, H., Styczynska, M., Winblad, B., Näslund, J., & Haroutunian, V. (2003). Amyloid β pathology in Alzheimer’s disease and schizophrenia. American Journal of Psychiatry, 160(5), 867-872.
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