Amyloid-Beta Oligomers — Newest Targets in the Fight Against Alzheimer’s Disease
By Sam Gandy, MD, PhD
Vol. 4 No. 4 P. 34
Alzheimer’s disease (AD) is the most common cause of the clinical syndrome of dementia, affects one-half of the 85-and-older population, and is responsible for about two-thirds of all dementia.
What Is Amyloid-β and What Are Oligomers?
Both inside and outside the cell, a substance called amyloid-β (Aβ) forms two type of structures in the brain during AD: stringlike fibers that build up to form the amyloid plaque and less organized clumps called oligomers. Oligomers and plaques seem to be on different pathways, and there is some evidence that drugs that turn oligomers into plaques might even be beneficial. This concept would’ve been nearly laughable 10 years ago. Now it seems likely to be true.
Focus on Amyloid-β Plaques and Amyloid-β Oligomers
Brain amyloid-β comes in various lengths, typically abbreviated as “short Aβ” for the form composed of 40 building blocks and “long Aβ” for the form composed of 42 building blocks. This long Aβ (also abbreviated Aβ42) is much stickier than the shorted Aβ40, and long Aβ is believed to initiate the formation of oligomers, fibrils, and plaques. Both long and short Aβ are products of normal metabolism of all cells in the body although the brain makes more than any other organ.
Genetic forms of AD all lead to Aβ with changes in the building blocks. These changes are called mutations, and they increase the stickiness of Aβ even further. The fact that genetic mistakes in amyloid can cause AD provides permanent, irrefutable proof that mistakes in amyloid metabolism can cause AD. In fact, of all the forms of AD that have been studied, the only starting point we are certain about involves amyloid metabolism. And any model of how AD occurs must account for why amyloid builds up.
Oligomer Buildup and Memory Problems
Neuropathologists have long recognized that amyloid plaque burden is a poor predictor of cognitive function at the time of death. As more refined techniques for measuring Aβ levels have become available, this correlation has been revisited again and again. More recently, brain and cerebrospinal fluid levels of Aβ oligomers have been reported to correlate closely with cognitive status. Scientists have also taken extracts from AD brain and applied the extract to nerve cells in a dish. When they looked at these extracts under the microscope, they were surprised to see that the extracts that killed the nerve cells in the dish were not filled with plaques but rather with oligomers.
New Discovery in Oligomer Science
My colleagues and I created a new mouse model that developed only oligomers and no plaques. Those mice could not form new memories very well. We then added a gene that would cause plaques to develop on top of the oligomers. These mice were still unable to form new memories well, but they were no worse off than the oligomer-only mice.
Finally, after the mice died, we measured the levels of oligomers in their brains. The severity of the memory problem was related to the levels of oligomers but had no relationship to the burden of plaque buildup. We concluded that oligomers are more important than plaques.
This is especially important as we develop new brain scans that show amyloid buildup. Even the newest research scans show only plaques and not oligomers. One goal of our research group is to develop brain scans that reveal oligomer buildup even before any memory problem develops. Someday, we may be able to perform “oligomer brain scans” that predict exactly who will develop AD and perhaps even predict when that will happen. We cannot do this yet, but we are optimistic that this may be possible.
Are Plaques Totally Unimportant?
Probably not. Our working model is very simplistic. There may well be oligomers trapped in plaques along with the stringy fibers. I don’t think we should discard plaques altogether, but I believe that beginning now, we must think about clearing out brain oligomers as well as brain plaques. However, it is clear that plaque-busting drugs will work only early in the disease process, probably prior to the onset of any symptoms. We might even need to start the drugs in middle life.
Advancing Alzheimer’s Research
Much more work is required to figure out AD. Unfortunately, the federal government is reducing the budget for Alzheimer’s research. The most helpful thing anyone can do right now is to contact legislators and advocate to them for sustaining—or even increasing—the AD research budget. Among AIDS, diabetes, cancer, heart disease, and dementia (all of which are worthy of research dollars), the National Institutes of Health allotment is least for AD, and by an enormous margin. Parity of the federal Alzheimer’s research funding allotment with that assigned to other major causes of morbidity and mortality would go a long way toward accelerating the development of an effective therapy or prophylactic for Alzheimer’s disease.
— Sam Gandy, MD, PhD, holds the Mount Sinai chair in Alzheimer’s disease research at the Mount Sinai School of Medicine in New York City as well as joint primary appointments as a tenured professor of neurology and of psychiatry. He is director of the Center for Cognitive Health and the NFL Neurological Center at Mount Sinai and is associate director of the National Institute on Aging-Designated Alzheimer’s Disease Research Center.