What does your doctor think?
This might apply to the naysayers:
“All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.”
- Arthur Schopenhauer, Philosopher
Could Soluble Amyloid Be Neuroprotective Rather Than Toxic? A New Study Provokes Strong Reactions
September 2, 2021
Article In Brief
A new study proposes that high cerebrospinal amyloid-beta 42 is associated with normal cognition in people with brain amyloidosis. But some independent experts questioned the paper's hypothesis.
Turning the standard amyloid hypothesis on its head, a study has found that higher levels of soluble amyloid-beta may be protective against cognitive impairment, rather than neurotoxic.
The cross-sectional study of nearly 600 people with brain amyloidosis enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) analyzed whether differences in their levels of soluble 42-amino acid beta amyloid (Abeta42) in cerebrospinal fluid would separate people with normal cognition from those with mild cognitive impairment (MCI) and Alzheimer's disease (AD).
Individuals with normal cognition had higher levels on average (864.00 picograms [pg]/mL) than those with MCI (786.60 pg/mL) or AD (617.46 pg/mL).Each standard deviation in Abeta42 was also associated with higher odds of normal cognition than AD (adjusted odds ratio, 6.26; p<0.001) or MCI (1.42; p=0.006).
“Everyone above the threshold of 800 pg/mL remained cognitively normal no matter how high their burden of amyloid plaque,” said the senior author of the study, Alberto J. Espay, MD, MSc, FAAN, professor of neurology at the University of Cincinnati Academic Health Center and director and endowed chair of the Gardner Family Center for Parkinson's Disease and Movement Disorders.
“If it's true that there is a level of soluble amyloid required for brain health, then we really need to test it, to confirm or refute it in a clinical trial,” Dr. Espay told Neurology Today. “If the hypothesis is correct, then raising soluble amyloid above 800 pg/mL should prevent, stabilize, or ideally reverse cognitive difficulties.”
Dr. Espay noted: “We didn't select patients based on early stage, but based on amyloid positivity, regardless of whether they were early or late, had dementia or not. We took all comers in the ADNI cohort, excluding only those participants who were PET negative for brain amyloid.”
The study, published on June 28 in The Lancet's open-access journal, EClinical Medicine, provoked unusually strong reactions from neurologists and neuroscientists familiar with its findings.
“It's strange to see a paper discussing amyloid, especially the soluble form, as something that could be potentially protective,” said Michelle Farrell, PhD, a postdoctoral research fellow in the department of neurology at the Athinoula A. Martinos Center for Biomedical Imaging at Harvard Medical School. “There are innumerable studies that make the point that it is toxic. It is very unlikely to be protective.”
But the paper also drew positive comments from neurologists and neuroscientists in the United States and abroad.
Joel S. Perlmutter, MD, FAAN, the Elliot Stein Family Professor of Neurology at Washington University, said in an email that the paper “could have important implications for the standard amyloid-beta cascade hypothesis and the whole notion of using PET imaging amyloid-beta as a biomarker of AD progression or clinical improvement—which have inadequate data backing them anyway.”
The study authors noted that the soluble precursor of Abeta42 peptide “is necessary for many essential functions—including copper homeostasis, regulation of mitochondrial function, brain development, and neuroprotection.
“In fact,” the paper noted, “as insoluble Ab42 accumulates with age in the brain, there is a corresponding decrease of soluble Ab42, as measured in the [CSF] of patients with sporadic and familial AD (due to PSEN1, PSEN2, or APP genetic mutations).”
The biggest clue that the amyloid hypothesis needs rethinking, the paper stated, is that none of the large clinical trials designed to lower soluble Abeta42 have produced clear evidence of benefit, and some have found harm.
“We already know that when Abeta42 is high, people are early in the course of their disease, and if you follow them over time, their Aβ42 levels are likely to drop.”—DR. SUZANNE SCHINDLER
“In these clinical trials, some of the people who took the medications to lower levels of Abeta42 became cognitively worse compared to placebo,” said Kariem Ezzat, PhD, a senior study author and biophysicist at the Karolinska Institute in Stockholm. “In my opinion, this is the strongest experimental evidence anyone could have.”
Dr. Ezzat compared the loss of function of soluble Abeta42 to the loss of insulin or growth hormone. “People with lower levels of insulin or growth hormone have disease,” he said. “We help them by giving them what they lack. But for Alzheimer's disease, we have never done that.”
“It's just another way of understanding the facts, that the disease is associated with lower levels of the soluble form of the Abeta42 protein,” he added. “Yet people are shocked when we say that a way forward is to replace the protein.”
Study Details
Using the ADNI data set, the researchers conducted a cross-sectional study of all 598 participants with brain amyloid plaques at the study's onset, as defined by PET-based standard uptake value ratio (SUVR) ≥ 1.08 for the radiotracer F-florbetaben or 1.11 for F-florbetapir. Higher SUVR indicated a greater burden of amyloid plaques.
In an analysis adjusted for participants' age, sex, education, APOE4, p-tau, t-tau, and centiloids levels, the study found a larger absolute effect size of soluble Abeta42 than for SUVR among participants with normal cognition (0.82 vs. 0.40) and among those with MCI (0.60 vs. 0.26) versus AD.
“In these clinical trials, some of the people who took the medications to lower levels of Abeta4 became cognitively worse compared to placebo. In my opinion, this is the strongest experimental evidence anyone could have.”—DR. KARIEM EZZAT
Higher levels of soluble Abeta42 were also associated with better neuropsychological function and larger hippocampal volume.
“This is the first study in humans assessing the mechanistic hypothesis that normal cognition among individuals with brain amyloidosis may require the preservation of high levels in the soluble Ab42 precursor, aiming to explain the paradox that normal cognition is possible in the setting of brain amyloidosis,” the paper stated.
The study authors concluded that data support the evaluation of strategies to increase soluble Abeta42 in amyloid PET-positive individuals with MCI or AD and in those whose CSF levels of Abeta42 are below the threshold of 800 pg/mL. Four of the study authors published another paper extending their arguments on June 12 in the Journal of Alzheimer's Disease. Dr. Espay also cited four papers, including two in the Journal of Neuroscience, showing that Abeta monomers are “neuroprotective” and “a critical requirement for the viability of central neurons.”
“If its true that there is a level of soluble amyloid required for brain health, then we really need to test it, to confirm or refute it in a clinical trial.”—DR. ALBERTO J. ESPAY
To begin testing their hypothesis in animal models, Drs. Ezzat and Espay have developed Abeta replacement therapies that are modified to lessen their transformation into plaques their arguments.
“We have formed a start-up company, REGAIN Therapeutics, and started preclinical testing in mice,” said Dr. Ezzat.
“We have encouraging preliminary data, not yet ready for publication. We are seeing some changes in the phenotype, the behavior, of some of the animals, but replication and additional studies are needed.”
Expert Commentary
Ruth Itzhaki, PhD, an emeritus professor at the University of Manchester and visiting professor at Oxford University in England, who has published dozens of studies exploring the association between AD and herpes simplex 1, said the paper's hypothesis regarding the role of soluble Abeta42 is “an interesting idea and the authors seem to bring perfectly good arguments for it; it shouldn't be derided or ignored by those who see it as heretical.”
Dr. Itzhaki added, however, “Certainly the people who wrote this paper need more experimental evidence.”
Abass Alavi, MD, professor of radiology and professor of neurology at the University of Pennsylvania, a pioneer of PET imaging and longtime critic of the standard amyloid hypothesis, said of the new paper, “I found it very much in line with what I've been saying for a long time.”
Others, however, were critical of the paper's theory.
“It is a major over-reach to suggest that reducing soluble Abeta42 directly causes cognitive deterioration,” said Suzanne Schindler, MD, PhD, a neurologist at the Washington University School of Medicine. “They're picking out people early in the course of Alzheimer's disease,” Dr. Schindler said. “That's why they look better, not because Abeta42 is protective.”
Dr. Schindler added that the idea that Abeta42 is protective is not outside of the mainstream way of thinking. “Just because something is correlated doesn't mean it is causative,” she said.
Dr. Farrell said: “This paper discusses soluble Abeta42 as if it is a normal and healthy precursor to the neurotoxic insoluble species, and that is counter to decades of research demonstrating that soluble Abeta42 is not only neurotoxic but the most neurotoxic species of Abeta. High CSF Abeta42 is most likely associated with better cognition because it is indicative of normal clearance of the neurotoxic soluble Abeta42 from the brain.”
“This paper discusses soluble Abeta42 as if it is a normal and healthy precursor to the neurotoxic insoluble species, and that is counter to decades of research demonstrating that soluble Abeta42 is not only neurotoxic but the most neurotoxic species of Abeta.”—DR. MICHELLE FARRELL
Disclosures:
Dr. Ezzat is cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies. Dr. Espay reports grants from NIH and the Michael J Fox Foundation. He has received personal fees from Abbvie, Neuroderm, Neurocrine, Acadia, Sunovion, US World Meds, UCB, Lippincott Williams & Wilkins, Cambridge University Press, Springer, Kyowa Kirin, and Amneal. In addition, Dr. Espay is cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies. Drs. Ferrell, Schindler, and Itzhaki had no disclosures.
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