Sarah Kazemeini, Ahmed Nadeem-Tariq, Ryan Shih, John Rafanan, Nabih Ghani, and Thomas A. Vida (all Medicine) published "From Plaques to Pathways in Alzheimer’s Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis" in the International Journal of Molecular Sciences.
Alzheimer’s disease (AD) is expected to impact over 13 million people in the United States alone by 2060. For years, the accumulation of amyloid-beta (Aβ) plaques in the brain has been the root cause of AD. This “amyloid cascade hypothesis” focused treatments on reducing Aβ, yet clinical trials consistently failed to slow cognitive decline significantly. This new critical review challenges the prevailing view of AD, which has long focused on Aβ plaques as the primary cause. The research team of five second-year medical students and Associate Professor Thomas Vida published the Mitochondrial-Neurovascular-Metabolic (MNM) hypothesis, offering a more comprehensive framework. Rather than focusing solely on Aβ, the MNM hypothesis highlights the role of three interconnected factors: mitochondrial dysfunction, neurovascular impairment, and metabolic disruptions. Mitochondrial dysfunction leads to reduced energy and oxidative stress, affecting neurons and accelerating cognitive decline. Neurovascular breakdown compromises the blood-brain barrier, allowing harmful substances to enter the brain, triggering inflammation. Additionally, impaired glucose metabolism limits brain energy, exacerbating AD symptoms. The MNM hypothesis offers a promising direction for treatments beyond single-target Aβ therapies, which have shown limited success. This approach could unlock new therapies, providing hope for slowing AD progression and enhancing the quality of life for millions worldwide.
