Have we been wrong about what causes Alzheimer’s disease? New research suggests yes.
For years, the leading theory for the cause of this neurodegeneration was the accumulation of abnormal proteins in and around our brain cells. One of the major components of these protein buildups was thought to be a protein called amyloid beta, or Aβ42, which clump together into what is known as amyloid plaques. However, a new study from the University of Cincinnati has thrown this hypothesis into doubt.
“We noticed that most of the population with amyloid plaques does not develop Alzheimer’s,” Alberto Espay, professor of neurology at the University of Cincinnati Academic Health Center, told Newsweek. “By the age of 85 years, only one fifth of those with amyloid plaques develop Alzheimer’s disease.”
Previous research from Espay’s lab has suggested that Alzheimer’s does not occur as a direct result of these plaques. Instead, it appears to occur when there is not enough Aβ42.
“Aβ42 is a protein that defends our brain from a variety of toxic and infectious exposures,” Espay said. “In the process of reacting, it transforms into amyloid plaques. Amyloid plaques is made of clumped up Aβ42. Once in amyloid, Aβ42 no longer works (the plaques can be viewed as a tombstone of Aβ42).”
In other words, Espay said that Alzheimer’s is a disease of loss: “We lose Aβ42. Every single person living with Alzheimer’s disease has low levels of Aβ42 whereas many of us have amyloid plaques in our brain and are cognitively normal.”
Many existing treatments for Alzheimer’s are based on the theory that amyloid plaque accumulation causes the disease. However, Espay said that the symptom relief seen from these drugs may be an indirect effect.
In a new study, published in the journal Brain, Espay and colleagues analyzed data from 26,000 individuals enrolled in 24 randomized clinical trials exploring the effects of new Alzheimer’s treatments. The trials assessed cognitive impairment and differences in levels of Aβ42 before and after treatment. What they found was that higher levels of Aβ42 after treatment were associated with slower cognitive decline.
“All stories have two sides—even the one we have told ourselves about how anti-amyloid treatments work: by lowering amyloid,” Espay said. “In fact, they also raise the levels of Aβ42. Even if this is unintended, it is why there may be a benefit. Our study shows that we can predict changes in cognitive outcomes in anti-amyloid trials at least as well by the increases in Aβ42 as by the decreases in amyloid.”
So why do some people with high levels of amyloid plaques not see the cognitive decline associated with Alzheimer’s? “We discovered that what keeps people with amyloid plaques cognitively normal is the extent to which they are able to produce enough Aβ42, an important protein for brain health, to keep it within normal levels,” Espay said.
These findings may open new avenues for future Alzheimer’s treatments. “If the problem with Alzheimer’s is the loss of the normal protein, then increasing it should be beneficial, and this study showed that it is,” Espay said. “The story makes sense: Increasing Aβ42 levels to within the normal range is desirable.”
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References
Sturchio, A., Dwivedi, A. K., Malm, T., Wood, M. J. A., Cilia, R., Sharma, J. S., Hill, E. J., Schneider, L. S., Graff-Radford, N. R., Mori, H., Nübling, G., El Andaloussi, S., Svenningsson, P., Ezzat, K., Espay, A. J., & Dominantly Inherited Alzheimer Consortia (DIAN) (2022). High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations. Journal of Alzheimer’s disease : JAD, 90(1), 333–348. https://doi.org/10.3233/JAD-220808
Espay, A. et al. (2024). Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer’s disease trials. Brain.
