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An artist’s representation of how the grid cell network tracks our position in space.

An artist’s representation of how the grid cell network tracks our position in space.

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Alzheimer’s disease tied to brain’s navigation network

The way you navigate a virtual maze may predict your chances of getting Alzheimer’s. That’s the conclusion of a new study, which finds that people at risk for Alzheimer’s have lower activity in a newly-discovered network of navigational brain cells known as “grid cells.” The finding could lead to new ways to diagnose this debilitating disorder.

The discovery of the grid cell network won the Nobel Prize in Medicine or Physiology last year. The neurons that make up the “grid” are arranged in a triangular lattice in the entorhinal cortex—a region of the brain used in memory and navigation. The “grid” activates in different patterns based on how individuals move, keeping track of our location in the coordinate plane.

 Researchers think the cells help create mental maps and allow us to navigate through space even in the absence of visual cues. “If you close your eyes and walk ten feet forward and turn right and walk three feet forward, the grid cells are believed to [track your position],” says neuroscientist Joshua Jacobs at Columbia University.

Intriguingly, people withthe so-called e4 variant of a gene known as APOE—the largest genetic risk factor for developing Alzheimer’s later in life—are at a higher risk for developing abnormalities in their entorhinal cortex. Because the grid cells are found in the same region, scientists wondered if the reason Alzheimer’s patients are more likely to get lost and have difficulty navigating could be explained by damage to the network.

The researchers recruited two groups of young adults without symptoms of Alzheimer’s. One carried a copy of the APOE-e4 variant whereas the other group did not. Participants were then asked to navigate a circular virtual arena. The space had blue sky, a few mountains in the distance, and a grass floor that was littered with everyday objects like basketballs and eggplants. Participants completed tasks that involved collecting the virtual objects and returning them to the same location at a later time. The team monitored the brain activity of each participant during the trial via functional magnetic resonance imaging (fMRI), a procedure that measures brain activity based on blood flow.

Grid cells themselves can’t be imaged directly with fMRI, but recent advances in the technology have allowed scientists to capture “grid-cell-like representations” which can be used as a proxy. As hypothesized, participants carrying the e4 version of the APOE gene showed fewer grid-cell-like representations than their peers while participating in the trial, the team reports online today in Science.

However, the at-risk group performed just as well in the arena. “Initially it seemed to be some sort of paradox,” says neuroscientist Nikolai Axmacher, a study author from Ruhr University  Bochum, in Germany. One idea is that the brain might be compensating with other areas, meaning the task of navigation is being performed outside of the grid cell network. Axmacher and his team also observed an uptick of activity in the hippocampus (a nearby brain region usually implicated in emotion and memory) during the trial, but only in the at-risk population that wasn’t relying on the grid-cell network. “This suggests that you can either use the grid cell system or you can use the hippocampus,” he says.

Interestingly, there were behavioral differences depending on which part of the brain participants used to navigate, hinting that the different systems use different strategies for spatial orientation: Participants with fewer grid-cell-like representations were more likely to keep to the edges of the virtual environment during the trial. The other group used the entire area. It will take more experiments to confirm any hypotheses, but perhaps something about navigating in the middle of the arena—with fewer visual landmarks—is more difficult without the grid cell activity.

"The potential implications of this work are interesting because they indicate that properly functioning grid cells are correlated with human spatial behavior,” says Jacobs, who was not involved with the study.

The results suggest that it may take more than knocking out the grid cell network to cause the navigation issues present in Alzheimer’s patients. But it also offers a potential new avenue of study. Alzheimer’s is among the most heavily studied diseases in the world, but researchers have had limited success in preventing or reversing the disease. Some scientists speculate that existing therapies could be more successful if they were delivered earlier in life—before the disease causes too much damage to the brain. While it’s probably unlikely that the navigational test will be used as an early diagnostic for Alzheimer’s in the near future, the insights into the disease’s progression and mechanism could be a step toward preventative therapies.