For decades, scientists have attributed the onset of Alzheimer’s disease to the buildup of abnormal proteins in the brain, particularly amyloid beta (Aβ42), which forms amyloid plaques. These plaques were believed to disrupt brain function, leading to memory loss and cognitive decline. However, a recent study from the University of Cincinnati is challenging this theory, suggesting that the accumulation of amyloid plaques might not be the primary driver of Alzheimer’s, and offering new hope for slowing the progression of the disease by focusing on protein regulation.
The Amyloid Beta Theory: Long-Standing But Now Questioned
Since the 1980s, the dominant theory in Alzheimer’s research was that amyloid beta proteins clump together to form plaques that disrupt communication between neurons. These plaques were thought to interfere with cell function, ultimately causing the death of brain cells. Scientists believed that by targeting these plaques, they could potentially slow or stop the progression of Alzheimer’s disease. Billions of dollars have been invested in research and drug development based on this hypothesis.
However, the results of amyloid-targeting drugs have been disappointing. Numerous clinical trials have failed to show significant improvements in cognitive function, despite effectively reducing amyloid plaques in the brain. This led researchers to question whether amyloid beta was truly the main culprit behind Alzheimer’s disease.
The new study from the University of Cincinnati adds to this growing skepticism. Led by Dr. Alberto Espay, a professor of neurology, the research team discovered that many people with amyloid plaques never develop Alzheimer’s disease, even in old age. According to Espay, by the age of 85, only one-fifth of individuals with amyloid plaques develop the disease, casting doubt on the idea that amyloid buildup is the direct cause.
“We’ve spent decades focusing on amyloid plaques as the villain, but it turns out that these plaques are not enough to explain the onset of Alzheimer’s,” Espay explained. “We need to look elsewhere for the underlying mechanisms.”
Instead of focusing on the accumulation of harmful proteins, Espay’s team suggests that Alzheimer’s may be linked to the body’s inability to regulate proteins effectively. Specifically, the researchers argue that increasing the levels of a healthy protein, amyloid beta 40 (Aβ40), could counteract the effects of Aβ42 and help maintain brain function.
Amyloid beta 40, unlike Aβ42, does not form harmful plaques and may have a protective role in the brain. Espay’s research found that individuals with higher levels of Aβ40 were less likely to develop Alzheimer’s, even if they had amyloid plaques. The findings suggest that boosting Aβ40 could restore the balance between different forms of amyloid beta, potentially preventing the toxic effects of Aβ42.
“Our study indicates that the ratio of these proteins, rather than their absolute levels, may be more important,” Espay said. “By increasing the amount of Aβ40, we might be able to protect brain cells from the damage caused by Aβ42, offering a new approach to treating Alzheimer’s.”
If Espay’s findings hold true, they could represent a paradigm shift in Alzheimer’s research. Instead of focusing solely on clearing amyloid plaques from the brain, future therapies may aim to restore the balance between different forms of amyloid beta proteins. This would mark a significant departure from decades of research centered on the amyloid cascade hypothesis.
Many experts believe this new approach could open the door to more effective treatments. By shifting the focus from reducing amyloid plaque to boosting protective proteins like Aβ40, researchers could develop drugs that slow or even prevent the progression of Alzheimer’s in its early stages.
While the idea of boosting healthy proteins to combat neurodegeneration is still in its infancy, several pharmaceutical companies are already exploring ways to increase Aβ40 levels. Some early-stage trials have shown promising results, suggesting that protein modulation could become a viable strategy in the fight against Alzheimer’s.
Espay’s study also raises important questions about the future direction of Alzheimer’s research. For years, funding and resources have been heavily directed toward amyloid-targeting therapies, but the failure of many of these treatments has led to calls for broader approaches.
“This study underscores the need for a more holistic understanding of Alzheimer’s disease,” said Dr. Richard Isaacson, a neurologist specializing in Alzheimer’s prevention. “We’ve been too focused on a single hypothesis for too long. It’s time to explore other mechanisms, such as protein regulation, inflammation, and metabolic factors, that could contribute to the disease.”
Isaacson and other experts point out that Alzheimer’s is a complex and multifactorial disease, with genetic, environmental, and lifestyle factors all playing a role. Moving forward, research will likely focus on a combination of approaches, including protein modulation, lifestyle interventions, and strategies to reduce inflammation in the brain.
For the millions of people affected by Alzheimer’s disease, Espay’s findings offer a glimmer of hope. While much work remains to be done, the idea that boosting healthy proteins could slow or prevent cognitive decline represents a promising new avenue for treatment.
“Alzheimer’s is a devastating disease, not just for the individuals who have it but for their families and caregivers,” Espay said. “We’re optimistic that by exploring new strategies, we can make real progress in slowing the disease and improving quality of life.”
In the meantime, patients and their families are encouraged to take proactive steps to reduce their risk of Alzheimer’s, including maintaining a healthy diet, engaging in regular physical and mental exercise, and managing conditions like diabetes and hypertension, which have been linked to cognitive decline.
Insights about protein regulation as a potential solution to Alzheimer’s disease mark a significant shift in the understanding of this complex condition. As researchers move away from the amyloid cascade hypothesis and explore new therapeutic avenues, there is renewed hope that the progression of Alzheimer’s can be slowed, or even halted. While the journey to find effective treatments continues, studies like Espay’s offer a hopeful glimpse into the future of Alzheimer’s research and care.
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., Abanto, J., Dwivedi, A., & Imbimbo, B. P. (2024). Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer’s disease trials. Brain. http://dx.doi.org/10.1093/brain/awae216