Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Centre (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads.
In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective.
"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A Small.
"But this study is the first to show in living patients that it 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," Small said.
The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation.
The researchers suspect 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.
A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist.
"The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitises 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.
The researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults. All were free of dementia at the time of enrollment.
"This study has given us a unique opportunity to image and characterise patients with Alzheimer's in its earliest, preclinical stage," said Small.
The study was published in the journal Nature Neuroscience.