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Metabolic Changes in the Entorhinal Cortex Found as Earliest Signs of Alzheimer's Disease



ANIMAL MODELS of Alzheimers disease and human brains offer evidence that Alzheimers disease spreads from the entorhinal cortex (yellow) to other cortical regions (red) — the perirhinal cortex and posterior parietal cortex.

Using fMRI in humans and mouse models of Alzheimer's disease, investigators observed metabolic changes in the entorhinal cortex, which they propose show the earliest signs of Alzheimer's disease.

The vulnerability of the entorhinal cortex to degeneration has been known for decades, but the mechanism that produces this fragility has remained obscure. Now, a paper in the Dec. 22 online edition of Nature Neuroscience has provided a clue by identifying weak metabolism in the lateral entorhinal cortex (LEC) as the earliest sign of dysfunction.

“We can now ask why this area of the hippocampus is vulnerable in Alzheimer's disease,” said Scott Small, MD, Boris and Rose Katz professor of neurology at Columbia University, who led the research team. “This work has produced novel molecular insights and, based on that, we're going to develop novel therapies.”

The entorhinal cortex has long been suspected to play a key role in the origin of Alzheimer's disease. A histological study reported in Science in 1984, for example, described a “specific cellular pattern of pathology” in the subiculum of the hippocampal formation and layers II and IV of the entorhinal cortex. However, the lateral and medial neurons of the structure project to different parts of the brain, and contain neurons distinct in their morphological and physiological features. Dr. Small, director of Columbia University's Alzheimer's Disease Research Center, hypothesized that early Alzheimer's disease might subvert one of these subregions of the entorhinal cortex more aggressively than the other, causing degeneration that then spreads through the hippocampus and other structures.


DR. SCOTT SMALL said the study results have led him to question the notion that tau is inherently toxic, which has been central to the prevailing amyloid cascade hypothesis about the origin of Alzheimers disease.


Dr. Small and his colleagues used high-resolution fMRI to measure cerebral blood volume (CBV) in 96 older adults free of dementia or mild cognitive impairment (MCI), who were followed for an average of 3.5 years. In that time, 12 developed mild Alzheimer's disease, while the remaining 84 were regarded as control subjects. By using an automated system for marking regions of interest, they were able to distinguish activity in the medial entorhinal cortex (MEC) from the LEC regions that blur together when fMRI images are examined manually. The 12 who developed MCI displayed metabolism about 25 percent lower, on average, in the LEC and the parahippocampal gyrus, compared with controls.

Using the neuropsin promoter system, the researchers also bred three colonies of transgenic mice. One colony expressed a pathological human tau transgene; another expressed a pathological amyloid precursor protein (APP) transgene; and a third expressed both. These colonies contained 127 mice younger than six months, and 103 mice older than six months.

The younger mice that expressed both APP and tau showed CBV reductions in the LEC. All the older mice that expressed tau displayed CBV reductions in the LEC, but not older mice that expressed APP only. Those that expressed both APP and tau displayed reductions in the lateral entorhinal cortex, perirhinal cortex (PRC), and posterior parietal cortex (PPC).

“These results suggest that tau alone, but not APP alone, can ultimately cause LEC dysfunction, and that APP expression acts to accelerate and potentiate tau toxicity in driving LEC dysfunction and the observed spread to the PRC and PPC,” the authors wrote.

The results have led Dr. Small to question the notion that tau is inherently toxic, which has been central to the prevailing amyloid cascade hypothesis about the origin of Alzheimer's disease.

“I'm starting to think that tau accumulation in the dendrites of the entorhinal cortex is not a pathology at all, but rather merely reflective of something special about the lateral entorhinal cortex,” he said.

For example, fan cells in the entorhinal cortex, with their lush dendritic branching, have unusually high metabolism — possibly the highest metabolism of any cells in the brain — and they employ large amounts of tau, which could account for the tau deposits found in that neighborhood. “In our paper, we end with the speculation that perhaps the reason why tau accumulates in the lateral entorhinal cortex is because there needs to be a lot of tau there to support the distinct features of the neurons,” Dr. Small said. “As a byproduct of that, you start to see accumulation. We know there is a lot of tau accumulation there that doesn't seem to be harming the entorhinal cortex, so it's worth considering that this high dendritic complexity reflects a need for a lot of tau.”

When first isolated in 1984, the amyloid-beta peptide was assumed to be pathological, Dr. Small observed. “Now we know that amyloid and APP get processed normally,” he said. “Amyloid-beta is needed for some things. The dendritic accumulation of tau in the lateral entorhinal cortex might reflect what normally happens there.”


The changes in metabolism detected in the entorhinal cortex of mice and humans is one of the most exciting aspects of the Nature Neuroscience paper, said Mark Mattson, PhD, chief of the Laboratory of Neurosciences at the National Institute on Aging, whose own research involves the molecular and cellular mechanisms of brain aging. Dr. Mattson was not involved with the current research.

“They found a hypermetabolic state as indicated by cerebral blood volume in the lateral entorhinal cortex,” Dr. Mattson said. “That suggests, as has been suggested for other neurodegenerative disorders, particularly amyotrophic lateral sclerosis, that their high demand for energy may make them particularly vulnerable as they age.”

A decline in cerebral blood volume in the lateral entorhinal cortex, and in subregions of the default mode network, correlates with the reduced neural activity observed in people with MCI and Alzheimer's disease.

“To my knowledge this is the first paper showing such a relationship,” Dr. Mattson said. “You have two regions affected very early in the disease process, and there seems to be some relationship between the two at the level of neuronal function. I think those are the two new findings that are most important.”

Dr. Mattson's own research has studied ways to maintain normal brain metabolism during the aging process through exercise and intermittent fasting, which has been shown to boost brain levels of brain-derived neurotrophic factor (BDNF), which declines in Alzheimer's and other types of neurodegeneration.

“BDNF is produced and released in an activity-dependent manner throughout the brain,” he said. “It plays important roles in synaptic plasticity, long-term potentiation, learning and memory. I'd bet it's quite important in the entorhinal cortex too.”

Dr. Mattson said he would like to see the mouse models that the authors used subjected to exercise or other interventions that might delay or ameliorate the alterations in cerebral blood volume and pathological changes. He would also like to see them tested for learning and memory alterations that could be compared with the imaging results.

“It would be interesting to take those animals and put running wheels in cages, or put them on intermittent fasting to see if that will delay or ameliorate the development of alterations in cerebral blood volume and pathological changes too,” he said.

This human study in Nature Neuroscience coincides with animal studies that show calorie restriction increases longevity and decreases morbidity, said Yonas E. Geda, MD, professor of neurology and psychiatry at the Mayo Clinic in Scottsdale, AZ.

Dr. Geda's own research has shown that high caloric intake appears to increase the risk of MCI among humans. He and his colleagues studied 1,072 cognitively normal elderly and 161 with MCI, all 70–92 years of age, drawn from the Mayo Clinic Study of Aging, a prospective analysis of cognitive decline among a large cohort of residents living in Olmsted County, MN.

While there was no significant difference between low and moderate calorie intake (up to 2,143 calories per day), the risk of having MCI nearly doubled for those who consumed more than 2,143 calories per day. “And the risk was amplified for people positive for apolipoprotein E4,” Dr. Geda said. “Furthermore, moderate caloric intake was not associated with MCI even among subjects who are apolipoprotein E4 carriers.” [The study was published in the Journal of Alzheimer's Disease in 2013.]

The Nature Neuroscience paper excelled at using neuroimaging to connect its findings from animal models to human pathology, said Jazmin Acosta, PhD, a research associate in Dr. Geda's Translational Neuroscience and Aging Program at the Mayo Clinic.

“The study was beautifully designed in that you see the essence of translational research,” she said. “The authors found interactions between tau and APP pathology using mouse models, which was also described in humans. You can see multiple lines of evidence converging to confirm pathological changes occurring in the lateral entorhinal cortex.”

Dr. Geda agreed. “This paper reinforces our conviction that the future of research is translational in nature,” he said. “That's the direction we should be heading.”


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