The entorhinal cortex may be the first brain region affected by Alzheimer’s pathology. It also happens to house specialized neurons called “grid cells” that control spatial navigation. As described October 22 in Science, researchers developed a spatial-navigation test to measure grid-cell function via functional magnetic resonance imaging (fMRI). They reported that the function of grid cells, as well as spatial navigation, faltered in healthy college students who carried the AD risk gene ApoE4. Despite these early deficits, spatial memory in the risk-carriers remained normal, perhaps due to compensatory hyperactivity detected in the neighboring hippocampus. The researchers, led by Christian Döller of Radboud University in Nijmegen, the Netherlands, and Nikolai Axmacher at the German Center for Neurodegenerative Diseases in Bonn, Germany, proposed that waning grid cell function and altered navigation could serve as very early warning signs of impending AD.
“We have long suspected that impairment in grid cells and the spatial map of the entorhinal cortex is responsible for the navigation problems often seen at the very earliest stages of Alzheimer’s disease,” commented Edvard and May-Britt Moser of the Kavli Institute for Systems Neuroscience in Trondheim, Norway, who were not involved in the study. “This is the first indication of such a relationship, and we see it as a major advance that will for sure benefit the search for the mechanisms of Alzheimer’s disease.” Grid cells define spatial orientation, and their discovery earned the Mosers the 2014 Nobel Prize in Physiology or Medicine.
While malfunctions in the memory-making hippocampus receive much of the blame for causing classical AD symptoms, the first pathological signs of the disease appear in its highly connected next-door neighbor, the entorhinal cortex. Tau neurofibrillary tangles have been spotted there as early as the third decade of life, and occur with greater frequency in people who carry the ApoE4 allele (see Braak and Del Tredici, 2011; Ghebremedhin et al., 1998).
In search of a proxy for entorhinal cortex health and perhaps an early marker of AD, first author Lukas Kunz and colleagues looked to grid cells, a specialized type of neuron exclusive to that brain area. Each grid cell fires when the subject of an experiment—say, a mouse—reaches a certain position in space. These positions form the vertices of equilateral triangles, much like the layout of a Chinese checkerboard. This grid-like firing pattern aids in spatial navigation, even in a pitch-black room. Problems with spatial navigation and memory often occur early in people with AD as well as in AD animal models.
Kunz and colleagues assessed grid cell function in people using an fMRI-based test developed previously by Döller (see Döller et al., 2010). In it, participants perform a spatial-navigation and memory task while neural activity is recorded via fMRI. Volunteers view a screen containing a circular arena bordered by cliffs in the distance, in which an everyday object such as a bucket transiently appears. The participants must then navigate to the previous location of the object. Until they find the correct spot, they are shown the object again and allowed to keep trying. The participants performed this series of tasks for eight objects over the course of an hour. From the initial fMRI recordings, the researchers established the orientation of the grid cell firing. Once that was known, the researchers calculated the “grid cell representation”—a measure of the difference in firing patterns across the right entorhinal cortex that occurs when participants navigate in alignment versus misalignment with that grid. This grid-cell representation serves as the ultimate readout for grid-cell function.
The researchers compared grid-cell representations in 38 ApoE4/E3 carriers and 37 ApoE3/E3 carriers. They found that grid-cell function was significantly impaired in people harboring an ApoE4 allele. ApoE4 carriers also navigated differently within the virtual arena. While all participants displayed a preference for the center of the arena, this partiality was weaker in ApoE4 carriers, who spent more time skirting the borders than non-carriers. This edge-hugging behavior inversely correlated with grid-cell function.
Spatial memory, as measured by how well each participant learned the location of objects, was similar between ApoE4 carriers and non-carriers, although the strength of spatial memorycorrelated with grid cell function as well as preference for the center of the arena.
Why was spatial memory spared in ApoE4 carriers? The researchers speculated that the hippocampus, which is also highly involved in spatial orientation and memory, could compensate for the functional impairment of the grid cells in the entorhinal cortex. Indeed, ApoE4 carriers displayed higher task-oriented activity in the hippocampus than non-carriers, and this elevated activity correlated with reduced grid-cell function and elevated spatial memory. Axmacher speculated that the ApoE4 carriers’ reduced preference for the center of the arena could be a consequence of this hippocampal compensation. Grid cells facilitate navigation in open spaces, while neurons in the hippocampus may rely on objects or boundaries to generate a sense of place, he told Alzforum.
The hippocampal compensation in ApoE4 carriers could ultimately wane as that region succumbs to pathology, Axmacher said. It is also possible that the ramped-up activity could facilitate hippocampal deficits or beckon AD pathology later on, he added.
In a joint comment to Alzforum, Eric Reiman of the Banner Alzheimer’s Institute in Phoenix and Richard Caselli of the Mayo Clinic in Scottsdale, Arizona, wrote that greater activity does not necessarily point to impending neurodegeneration. However, in support of this notion, a previous study from Reiman did find elevated hippocampal activity in presymptomatic carriers of the familial AD variant of presenilin (see Reiman et al., 2012).
Axmacher proposed that grid-cell representations and/or spatial-navigation tests could serve as early detectors of incipient AD pathology. He plans to try the tests on older people and those at different stages along the AD spectrum, from subjective cognitive decline to mild cognitive impairment to AD. The test needs to be shortened for older, symptomatic people, who are less likely to tolerate an hour of spatial memory tasks confined within an MRI machine, he added.
Other researchers have also created human versions of spatial-memory tests typically done with mice, including a Morris “land” maze test as well as virtual-reality tests, but these do not assess entorhinal grid-cell function directly (see Jan 2013 conference news; Cushman et al., 2008; Tangen et al., 2015).
Reiman and Caselli noted that in addition to the deficits in grid-cell function identified in this study, other neurodevelopmental differences have been reported in ApoE4 carriers, some as young as infants (see Dec 2013 news). “Given how early such findings appear, it seems they are more likely developmental than degenerative in origin, although it may well be that developmental differences predispose to degenerative changes at older ages,” they wrote (see Aug 2015 conference news). Further work will be needed to determine whether flagging grid cell function is a sign of pending neurodegeneration.
Dorene Rentz of Brigham and Women’s Hospital in Boston agreed. “The findings of reduced grid-cell-like representations in the right entorhinal cortex may be a critically important factor in exploring spatial disorientation in AD. Whether this will be useful for preclinical detection is unclear,” she wrote. “Further work will need to be done to explore these findings in amyloid-positive older adults, either through amyloid imaging or CSF. Merely having subjects with E4 does not necessarily mean ‘preclinical’ AD.”—Jessica Shugart
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