Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer’s disease and in mouse models of the disease, researchers at Columbia University Medical Center (CUMC) claim in an recent paper to have clarified three fundamental issues about Alzheimer’s: where it starts, why it starts there and how it spreads (Khan UA et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease.
Nat Neurosci. 2014;17:304) .
Alzheimer’s disease starts in the entorhinal cortex. Using fMRI in mouse and human brains, the researchers provide evidence that the disease spreads from the entohrinal cortex to other cortical regions — the perirhinal cortex and posterior parietal cortex.
The entorhinal cortex region of the brain has been known for a long time to be implicated in the early stages of Alzheimer’s disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP).
The CUMC study is however the first to show in living patients that the process begins specifically in the lateral entorhinal cortex, or LEC. This 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 could also be affected.”
In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults, all of whom were free of dementia at the time of enrollment. The adults 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 (CBV) — a measure of metabolic activity — in the LEC compared with that of the 84 adults who were free of dementia.
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, the 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 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 Dr
The study also addressed the role of tau and 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 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.