Like any invader, Alzheimer’s disease must gain a foothold before venturing more deeply into enemy territory. To date, reconnaissance has shown that Alzheimer’s starts in the entorhinal cortex. Now, however, higher-resolution imaging has made it possible to pinpoint Alzheimer’s origin, locating it in the lateral entorhinal cortex, or LEC. This intelligence, besides pointing to improved early warning systems that could trigger earlier, more effective counterattacks, also provides clues about Alzheimer’s preclinical spread. For example, it appears that Alzheimer’s spreads functionally—that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

High-resolution functional MRI (fMRI) was used to image patients with Alzheimer’s disease and in mouse models of the disease by researchers at Columbia University Medical Center (CUMC). These researchers published the results of their work December 22 in Nature Neuroscience, in an article entitled “Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease.”

The article’s co-senior author, Scott A. Small, M.D., noted that a community-based study, the Washington Heights-Inwood Columbia Aging Project (WHICAP), allowed the researchers to follow a large group of healthy elderly individuals, some of whom eventually developed Alzheimer’s disease. “This study,” said Dr. Small, “has given us a unique opportunity to image and characterize patients with Alzheimer’s in its earliest, preclinical stage.”

The 96 adults enrolled in the study were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer’s disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume—a measure of metabolic activity—in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and amyloid precursor protein (APP) in LEC dysfunction. 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.

To answer this question, the CUMC researchers 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.

In evaluating this result, the article’s authors asked themselves whether it was consistent with any of the mechanisms used to explain the early spread of Alzheimer’s from the entorhinal cortex. Of the two leading mechanisms—functional spread and trans-synaptic spread—functional spread seemed more likely. Trans-synaptic spread, the authors noted, had been shown in previous studies by expressing either APP or tau in the entorhinal cortex of mice, and observing changes in distal sites connected to the entorhinal cortex. The authors, however, wrote, “We did not observe clear evidence of worsening histological changes in distal regions of the mice expressing tau and APP.”

“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, Ph.D.

The study has implications for both research and treatment. “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. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer’s drugs during the disease’s early stages.

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