Alzheimer’s patients with different medical histories might possess distinct variants of amyloid beta fibrils—the basic component of the plaque-like deposits found in the brains of people with the disorder—according to study of two affected individuals published online today in the journal Cell. The findings hint at the existence of Alzheimer’s disease subcategories, and suggest a potential path forward to improving the diagnostic specificity of this devastating illness.
It’s thought by some scientists that the overproduction of amyloid beta peptides, or perhaps the failure to clear this peptide, can cause an accumulation of these molecules and the formation of fibrils in the brain, possibility leading to inflammation and neurotoxic effects.
Previous studies demonstrated that amyloid beta fibrils cultured in a test tube can present different molecular structures and can retain these structures when grown from short fibril fragments. To determine if different structures of these peptide chains are also present in human brains, the study’s researchers gently extracted amyloid fibrils from postmortem brain tissue taken from two Alzheimer’s patients who had different medical histories. One of the individuals received an Alzheimer’s diagnosis while still alive. The other was had initially been diagnosed with another form of dementia, but an autopsy that revealed the hallmark amyloid plaques in his her brain that indicated Alzheimer’s.
The researchers then used the extracted amyloid beta fibrils to seed the growth of isotopically-labeled amyloid samples in sufficient quantity for analysis. A close inspection of the peptides revealed that the fibrils grown from one patient seemed to have a periodic twist in their structure that was absent from those grown from the other patient’s sample, which grew fibrils with a constant diameter of 7 nanometers. Importantly, each of the patients possessed a single type of structure that did not overlap with that found in the other.
Robert Tycko, a chemist at the US National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, and co-author of the study, thinks that it’s likely that the fibrils found in any given individual with Alzheimer’s will be homogenous: “If the patients had more than one variant, “they would represent less than 10 percent of the amyloid beta fibrils.”
Chain of thought
This study could advance our understanding of how amyloid beta fibrils form in the brain. “One thing,” Tycko says, “could be that they develop at a specific site and then spread throughout the brain by a self-propagation mechanism.” The researchers also think there might be a correlation between fibril structure and the manifestation of the disease, although Tycko is quick to emphasize that “this is just a suggestion.” He and his colleagues are now screening a variety of patients to see if they can reproduce the results.
If other studies confirm the researchers’ findings, Alzheimer’s disease could soon join the emerging cluster of illnesses—such as cancer and autism—that are becoming more fractured because of advancements in research and technology. “These findings are very interesting,” says Gal Bitan, a neurologist at the University of California, Los Angeles, who did not participate in this study. Yet it will be hard to know whether the patients’ varying medical histories have anything to do with the disease’s presentation, Bitan says. “I will say, however, that this fits with what others are finding—that this is a very heterogeneous disease.”
Scientists have previously found that individuals who have two copies of the APOE4 appear more prone to early-onset Alzheimer’s. But Tycko says it’s too soon to link the findings of the study to a particular genotype: “It’s conceivable that the APOE 4 gene could lead to a distinct structure but there is no reason to suggest that yet.”
The discovery from Tycko’s team might help improve Alzheimer’s diagnostics using positron emission tomography (PET) scans by possibly leading to new intravenous imaging agents that could bind to specific fibril types, indicating exactly which structure is present in the brain. New drugs that inhibit the growth of certain amyloid beta fibril variants could also be on the horizon, although Tycko does not think drug developers will explore these avenues just yet. “I think pharmaceutical companies are more interested in drugs that inhibit production of the amyloid beta peptide in the first place.”