Alzheimer’s Disease Tracked From The Beginning
December 23, 2013

Changes Responsible For Alzheimer’s Development Discovered

redOrbit Staff & Wire Reports - Your Universe Online

By combining high-resolution functional MRI (fMRI) imaging scans in Alzheimer’s disease patients with mouse models of the neurodegenerative condition, researchers from Columbia University Medical Center (CUMC) have gained new insights into how, where and why the disease starts and spreads.

The study, which was published Sunday in the online edition of Nature Neuroscience, will help enhance the medical community’s understanding of Alzheimer’s, improve early detection of the disease, and shed light on which drugs are most effective in treating the disorder.

“It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex,” explained co-senior author Dr. Scott A. Small, director of the CUMC Alzheimer's Disease Research Center as well as a professor of neurology and radiology.

The study “is the first to show in living patients that it begins specifically in the lateral entorhinal cortex,” he added. “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 also demonstrated that the disease spreads over time from the LEC directly to the cerebral cortex, including the region known as the parietal cortex, which is involved in spatial orientation and navigation. Dr. Small and his colleagues believe that Alzheimer’s spreads “functionally,” meaning that it compromises the function of neurons in the LEC which then compromises adjoining neurons.

The study also determined that LEC dysfunction typically occurs when there are changes to both the tau protein and the amyloid precursor protein (APP). Since the LEC normally accumulates tau, it is particularly vulnerable to Alzheimer’s disease, explained co-senior author and CUMC professor Dr. Karen E. Duff. Tau accumulation also sensitizes that region of the brain to APP accumulation, and when they co-exist, the proteins can damage neurons in the LEC.

The researchers used a high-resolution fMRI variant in order to map metabolic defects in the brains of 96 patients enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). While they were dementia-free at the start of the study, some of them went on to develop Alzheimer’s, Dr. Small said. He added that the research gave his team “a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage.”

Each of the study participants were studied for an average of 3 1/2 years, at which time it was discovered that 12 of them developed mild Alzheimer's disease. An analysis of baseline fMRI images from each of those individuals revealed significant decreases in a measure of metabolic activity known as cerebral blood volume (CBV).

“A second part of the study addressed the role of tau and APP in LEC dysfunction,” CUMC said. “While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.”

The researchers created three mouse models in order to further study this matter. One of the mouse models had elevated levels of tau in the LEC, while another had elevated levels of APP and a third had elevated levels of both proteins. The LEC dysfunction was found to occur only in 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,” Dr. Small concluded.