New Research Challenges Long-Held Theory about Causes of Alzheimer’s Disease, Creating the Possibility of Useful New Biomarkers for Clinical Laboratory Tests
University of Cincinnati researchers hypothesize that low levels of amyloid-beta protein, not amyloid plaques, are to blame
New research from the University of Cincinnati (UC) and Karolinska Institute in Sweden challenges the prevailing theory about the causes of Alzheimer’s disease, suggesting the possibility of new avenues for the development of effective clinical laboratory assays, as well as effective therapies for treating patients diagnosed with Alzheimer’s.
However, in their findings published in the Journal of Alzheimer’s Disease, titled “High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations,” the researchers advanced an alternative hypothesis—that Alzheimer’s is instead caused by “depletion” of a soluble form of that same amyloid-beta protein.
“The paradox is that so many of us accrue plaques in our brains as we age, and yet so few of us with plaques go on to develop dementia,” said Alberto Espay, MD, one of the lead researchers of the study, in another UC news story. Espay is Professor of Neurology at the UC College of Medicine and Director and Endowed Chair of the Gardner Center for Parkinson’s Disease and Movement Disorders.
“Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies,” he added.
“It’s only too logical, if you are detached from the biases that we’ve created for too long, that a neurodegenerative process is caused by something we lose, amyloid-beta, rather than something we gain, amyloid plaques,” said Alberto Espay, MD (above), in a University of Cincinnati news story. “Degeneration is a process of loss, and what we lose turns out to be much more important.” The UC study could lead to new clinical laboratory diagnostics, as well as treatments for Alzheimer’s and Parkinson’s diseases. (Photo copyright: University of Cincinnati.)
High Levels of Aβ42 Associated with Lower Dementia Risk
In their retrospective longitudinal study, the UC researchers looked at clinical assessments of individuals participating in the Dominantly Inherited Alzheimer Network (DIAN) cohort study. DIAN is an ongoing effort, sponsored by the Washington University School of Medicine in St. Louis, to identify biomarkers associated with Alzheimer’s among people who carry Alzheimer’s mutations.
The researchers found that study participants with high levels of a soluble amyloid-beta protein, Aβ42, were less likely to develop dementia than those with lower levels of the protein, regardless of the levels of amyloid plaques in their brains or the amount of tau protein—either as phosphorylated tau (p-tau) or total tau (t-tau)—in their cerebral spinal fluid. P-tau and t-tau are proteins that form “tau tangles” in the brain that are also associated with Alzheimer’s.
One limitation of the study was that the researchers were unable to include Aβ40, another amyloid-beta protein, in their analysis. But they noted that this “did not limit the testing of our hypothesis since Aβ40 exhibits lower fibrillogenicity and lesser depletion than Aβ42, and is therefore less relevant to the process of protein aggregation than Aβ42.” Fibrillogenicity, in this context, refers to the process by which the amyloid-beta protein hardens into plaque.
While the presence of plaques may be correlated with Alzheimer’s, “Espay and his colleagues hypothesized that plaques are simply a consequence of the levels of soluble amyloid-beta in the brain decreasing,” UC news stated. “These levels decrease because the normal protein, under situations of biological, metabolic, or infectious stress, transform into the abnormal amyloid plaques.”
The UC News story also noted that many attempts to develop therapeutics for Alzheimer’s have focused on reducing amyloid plaques, but “in some clinical trials that reduced the levels of soluble amyloid-beta, patients showed worsening in clinical outcomes.”
New Therapeutics for Multiple Neurodegenerative Diseases
Eisai, a Japanese pharmaceutical company, recently announced phase three clinical trial results of lecanemab, an experimental drug jointly developed by Eisai and Biogen, claiming that the experimental Alzheimer’s drug modestly reduced cognitive decline in early-stage patients, according to NBC News.
Espay noted that lecanemab “does something that most other anti-amyloid treatments don’t do in addition to reducing amyloid: it increases the levels of the soluble amyloid-beta.” That may slow the process of soluble proteins hardening into plaques.
Beyond their findings about Alzheimer’s, the researchers believe similar mechanisms could be at work in other neurodegenerative diseases such as Parkinson’s disease, where the soluble alpha-synuclein protein also hardens into deposits.
“We’re advocating that what may be more meaningful across all degenerative diseases is the loss of normal proteins rather than the measurable fraction of abnormal proteins,” Espay said. “The net effect is a loss not a gain of proteins as the brain continues to shrink as these diseases progress.”
Espay foresees two approaches to treating these diseases: Rescue medicine, perhaps based on increasing levels of important proteins, and precision medicine, which “entails going deeper to understand what is causing levels of soluble amyloid-beta to decrease in the first place, whether it is a virus, a toxin, a nanoparticle, or a biological or genetic process,” according to UC News. “If the root cause is addressed, the levels of the protein wouldn’t need to be boosted because there would be no transformation from soluble, normal proteins to amyloid plaques.”
Clinical Laboratory Impact
What does this mean for clinical laboratories engaged in treatment of both Alzheimer’s and Parkinson’s patients? A new understanding of the disease would create “the opportunity to identify new biomarkers and create new clinical laboratory tests that may help diagnose Alzheimer’s earlier in the disease progression, along with tests that help with the patient’s prognosis and monitoring his or her progression,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report.
Given the incidence of Alzheimer’s disease in the population, any clinical laboratory test cleared by the FDA would be a frequently-ordered assay, Michel noted. It also would create the opportunity for pathologists and clinical laboratories to provide valuable interpretation about the test results to the ordering physicians.