By its final stages, Alzheimer’s disease (AD) leaves the entire brain in a degenerated state. In an effort to hit it before it spreads, scientists have been trying to determine the precise site in the brain where AD begins.
It appears that researchers at Columbia University have done just that. They have successfully pinpointed a brain region known as the lateral entorhinal cortex, or LEC. The LEC serves as a “gateway” of information flow to the memory centers of the brain, including the hippocampus and cerebral cortex.
Using functional magnetic resonance imaging (fMRI), the research team found that the LEC is the first area that accumulates levels of the amyloid-beta and tau proteins during Alzheimer’s disease.
Too much amyloid-beta causes plaque formation, while too much tau causes tangle formation, both of which rob brain cells of their normal function.
The study followed a large group of healthy elderly individuals at the time of enrollment, some of whom went on to develop AD.
When amyloid-beta and tau interact in the same cell, they trigger a cascade of events that lead to cellular dysfunction and cognitive decline.
The researchers discovered that cellular dysfunction spreads from the LEC to other parts of the cerebral cortex, including the parietal cortex, an area critical for spatial orientation and navigation. The gradual spread of AD to other parts of the brain suggested that the damaged LEC cells compromise the integrity of other neurons in adjacent areas of the brain.
The study followed a large group of healthy elderly individuals at the time of enrollment, some of whom went on to develop AD. Images of diseased brains were sampled from 96 adults participating in the Washington Heights-Inwood Columbia Aging Project (WHICAP).
An analysis of the baseline fMRI images of 12 individuals with AD found significant decreases in cerebral blood volume — an indicator of unhealthy metabolic activity — in the LEC compared with the 84 adults who were free of dementia.
Still, the results did not explain why the disease starts in the LEC. What makes LEC cells more susceptible to AD compared with any other type of brain cells?
To answer this question, the researchers studied the role of amyloid-beta and tau in the LEC of genetically engineered mice and discovered that the LEC is the first site where both amyloid-beta and tau are expressed in toxic amounts.
The hope is that the results will pave the way for a more accurate diagnosis of AD during presymptomatic stages — before there is any significant brain degeneration.
“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 Scott Small, senior author of the study and director of the Alzheimer's Disease Research Center at Columbia University.
This study is published online in advance of publication in the journal Nature Neuroscience.