Researchers from Columbia University Medical Center (CUMC) have used high-resolution functional MRI (fMRI) imagining of patients with Alzheimer’s and have classified three fundamental issues regarding the disease: where it starts, why it starts there, and how it spreads. These findings, which were published in the online edition of the journal Nature Neuroscience, could advance the understanding of Alzheimer’s and help with early detection, when drugs are most used.
Senior coauthor, Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer’s Disease Research Center said, “this study is the first to show in living patients that it [Alzheimer’s] begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected.”
The study shows that over time, the disease spreads from the LEC directly to other parts of the cerebral cortex, specially the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. Researchers believe that Alzheimer’s spreads functionally, meaning it compromises the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.
The third major finding in the study is that when changes in tau and amyloid precursor protein (APP) co-exist, LEC dysfunction occurs. “The LEC is especially vulnerable to Alzheimer’s because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer’s,” said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology at CUMC and at the New York State Psychiatric Institute.
For the study, a high-resolution variant of fMRI was used to map diabolic defects in the brains on 96 patients that were enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). At the time of enrollment, all patients were free of dementia.
These 96 adults were followed for 3.5 years, and 12 patients were found to have progressed to a mild form of Alzheimer’s. There was a significant decreases in cerebral blood volume (CBV) in the LEC in the 12 individuals as compared with that of the 84 adults who were free of dementia.
Researchers also wanted to address the role of tau and APP in LEC dysfunction. Usman Khan, an MD-PhD student based in Dr. Small’s lab, explained that to answer this question, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.
“Now that we’ve pinpointed where Alzheimer’s starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer’s at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions,” said Dr. Small.