Unlocking the Mystery: How Amyloid Plaques Fuel Alzheimer’s Disease!
amyloid plaques alzheimers research
New Study Questions If Amyloid Plaques Cause Alzheimer’s
Emerging Insights into Alzheimer’s Treatment: Elevated Aβ42 Levels Correlate with Cognitive Improvement
Recent research indicates that increasing concentrations of the brain protein amyloid-beta 42 (Aβ42) may more accurately account for the cognitive enhancements observed with novel Alzheimer’s therapeutics than the traditional focus on amyloid plaque reduction. This revelation challenges longstanding paradigms in Alzheimer’s disease management.
A comprehensive study demonstrates that the augmentation of Aβ42 protein levels, resulting from innovative Alzheimer’s medications, potentially explains the deceleration of cognitive deterioration as effectively as the diminution of amyloid plaques.
In an investigation scrutinizing the efficacy of newly sanctioned monoclonal antibodies in mitigating cognitive decline among Alzheimer’s patients through amyloid clearance, researchers from the University of Cincinnati identified that an inadvertent increase in a pivotal brain protein’s concentration is equally strongly associated with cognitive benefits.
Under the leadership of Dr. Alberto Espay from the University of Cincinnati, the findings were published in the journal Brain.
amyloid plaques alzheimers research: Study Background
For decades, the dominant hypothesis within the scientific community has posited that amyloid-beta 42 (Aβ42), a protein composed of 42 amino acids, aggregates into amyloid plaques. These plaques are believed to inflict damage on the brain, thereby precipitating Alzheimer’s disease.
Dr. Espay and his team propose that the normal, soluble form of Aβ42 is essential for neuronal health. They suggest that it is the depletion of Aβ42, rather than plaque accumulation, that drives Alzheimer’s pathology. This perspective is supported by existing research indicating that dementia arises not merely from high plaque levels but specifically when Aβ42 concentrations fall significantly.
Espay’s research posits that the conversion of Aβ42 into plaques is a physiological response of the brain to biological, metabolic, or infectious stressors. “Most individuals accumulate amyloid plaques as they age, yet only a minority with plaques develop dementia,” stated Espay, a professor of neurology and director at the UC Gardner Neuroscience Institute. “Nonetheless, plaques remain the focal point in biomarker development and therapeutic strategies.”
amyloid plaques alzheimers research: Study Details
Recently, several monoclonal antibody treatments designed to eradicate amyloid from the brain received approval after demonstrating a reduction in cognitive decline during clinical trials.
Espay and his colleagues observed that these medications unintentionally elevated Aβ42 levels. “Amyloid plaques themselves do not cause Alzheimer’s. However, excessive production of amyloid during the brain’s defense against infections, toxins, or biological changes can deplete Aβ42 below a critical threshold,” Espay elucidated. “This depletion is when dementia symptoms manifest.”
The research team analyzed data from nearly 26,000 participants across 24 randomized clinical trials involving these antibody treatments. They assessed cognitive impairment alongside Aβ42 level variations pre- and post-treatment. The analysis revealed that elevated Aβ42 levels post-treatment were independently linked to slower cognitive decline and reduced clinical deterioration.
“Every narrative has dual facets—even our understanding of anti-amyloid treatments functioning solely by reducing amyloid,” Espay remarked. “In reality, these treatments also elevate Aβ42 levels. Regardless of intent, this elevation may confer benefits. Our study indicates that cognitive outcomes in anti-amyloid trials can be predicted as effectively by Aβ42 increases as by amyloid decreases.”
Espay contends that these findings align with his overarching hypothesis regarding Alzheimer’s etiology, where heightened Aβ42 levels correlate with cognitive improvement. “If Alzheimer’s stems from the loss of normal protein function, then augmenting Aβ42 should be advantageous, and our study affirms this,” he stated. “The narrative is coherent: Restoring Aβ42 to normal levels is desirable.”
Nonetheless, Espay acknowledges that these results pose a dilemma for clinicians, as amyloid removal may prove toxic and potentially accelerate brain atrophy post-antibody treatment. “Should we administer anti-protein therapies to boost protein levels? I believe that the ultimate goal of increasing Aβ42 does not justify the means of reducing amyloid,” Espay remarked. Consequently, therapies aimed at directly increasing Aβ42 levels without targeting amyloid are a primary research focus for his team.
Reference
“Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer’s disease trials” by Jesus Abanto, Alok K Dwivedi, Bruno P Imbimbo, and Alberto J Espay, 11 September 2024, Brain. DOI: 10.1093/brain/awae216
Dr. Alberto J. Espay has received grant support from the NIH and the Michael J. Fox Foundation; personal compensation as a consultant and scientific advisory board member for Neuroderm, Amneal, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Sunovion, Supernus (formerly USWorldMeds), and Herantis Pharma; personal honoraria for speaking engagements for Avion, Amneal, and Supernus; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He co-founded REGAIN Therapeutics and is a co-inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies.” Bruno P. Imbimbo is an employee at Chiesi Farmaceutici and is listed among the inventors of several of the company’s patents for anti-Alzheimer drugs. The other authors declare no competing interests.
