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, 2011Ghebremedhin 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.

Off the Grid?

While lying in a brain scanner, participants "navigated" to the location where they remembered seeing an object. All the while, grid cell function was recorded using fMRI. [Courtesy of Kunz et al., Science 2015.]

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 


  1. Kunz and colleagues report that entorhinal grid-cell function in young adult APOE e4 carriers is deficient relative to non-carriers. To put this in perspective, some background may be helpful. The close correlation between neuronal activity and spatial navigation in behaving rats led to the identification of place cells that, when sought in humans (with intracortical electrodes in neurosurgical patients), led to the distinction between hippocampal neurons sensitive to spatial location and parahippocampal neurons sensitive to specific landmarks (Ekstrom et al., 2003). Grid cells, in turn, are entorhinal neurons whose activity connects with hippocampal neurons with “place” characteristics (Jacobs et al., 2013). The hippocampus receives spatial and non-spatial input from the entorhinal cortex adding a precise spatiotemporal context to an experience (Knierim, 2015). In a carefully planned series of fMRI studies, Kunz et al. identified that young adult APOE e3/4 heterozygotes have deficient grid-cell-like responses relative to their e3/3 age mates. The age range of participants was 18 to 30 years, and performance on actual spatial memory tasks—although correlated with grid-cell responses—was unimpaired in the e4 carriers. The authors went on to demonstrate that increased hippocampal activity compensated for this grid-cell weakness. Previous studies comparing BOLD signal from APOE e4 carriers and non-carriers have been inconsistent with regard to whether medial temporal activation is enhanced or diminished in e4 carriers (Trachtenberg et al., 2012). Even so, a potentially important implication of this work is that chronically enhanced hippocampal activity may predispose to neurodegeneration and thus represent a potential therapeutic target for prevention.

    This finding raises several clinically important questions:

    1. Is deficient spatial navigation or spatial memory an early manifestation of AD?

    Yes, but … bilateral hippocampal ablation, whether surgical or degenerative, results in a global amnestic syndrome that is clinically disabling, but seemingly no more so for spatial navigation than word-list learning. Spatial-memory impairment is not a unique early feature of AD, though it is certainly affected. However, this more likely represents a memory disorder than a spatial disorder. In contrast, visual variant AD is associated with asymmetric and highly disproportionate atrophy of posterior-visual-association cortices, not simply medial-temporal-lobe atrophy, and it produces severe visuospatial problems (simultanagnosia). Another visual syndrome in some patients with dementia, progressive prosopagnosia, results from frontotemporal lobar degeneration associated with TDP-43 inclusions. While this may impair the recognition of familiar landmarks, it does not produce the type of spatial navigational problems that typify patients with visual variant AD.

    2. Since this deficiency was observed in young APOE e4 carriers, are e4 carriers handicapped?

    While some studies have purported to show a difference, our own data have failed to demonstrate that e4 carriers have any handicap in educational, occupational, or financial attainment as young and working adults (Caselli et al., 2002). Whether this might reflect the compensation the authors demonstrate is unclear but certainly seems possible.

    3. Is this neuronal overactivity causing neurodegeneration?

    Excitotoxicity is an established mode of neuronal injury, but greater activity per se does not necessarily lead to neurodegeneration. The most bioenergetically active brain region, the striate cortex, is also the least vulnerable and least affected by AD. On the other hand, in a related study, Reiman and colleagues found greater right hippocampal activation on an fMRI task in presymptomatic PSEN1 carriers destined for neurodegeneration than non-carriers (Reiman et al., 2012). Assuming the grid-cell finding is developmental, it is difficult to know whether the accentuated hippocampal activity should be regarded as pathological or physiological. The vulnerability to future degeneration is clear, so  it seems reasonable to ask whether this might be a potential target for preventive therapy.

    4. Is this grid-cell deficiency an early sign of AD?

    A number of studies have identified alterations in young adults that have been correlated with either subsequent AD (Snowdon et al., 1996) or APOE e4 carrier status (Reiman et al., 2004; Bartzokis et al., 2006; Valla et al., 2010), and APOE-related differences have even been identified in infants (Dean et al., 2014). 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.


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    . Direct recordings of grid-like neuronal activity in human spatial navigation. Nat Neurosci. 2013 Sep;16(9):1188-90. Epub 2013 Aug 4 PubMed.

    . From the GPS to HM: Place cells, grid cells, and memory. Hippocampus. 2015 Jun;25(6):719-25. Epub 2015 Apr 15 PubMed.

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    . Apolipoprotein E and intellectual achievement. J Am Geriatr Soc. 2002 Jan;50(1):49-54. PubMed.

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  2. This study is an excellent example of basic neuroscience being extended to clinical relevance, and it presents a number of intriguing questions nicely detailed by Drs. Caselli and Reiman above. I would like to point out two additional areas of relevant research.

    First, with regard to neuronal overactivity and its relationship to AD pathophysiology, there was an excellent study by Yamamoto et al. using optogenetic tools in APP transgenic mice to chronically increase firing in lateral entorhinal cortex neurons projecting to the dentate gyrus. This overactivation strongly increased amyloid deposition in the dentate gyrus. Hence, it is quite reasonable, as might be expected based on the link between amyloid production and synaptic activity (even under normal physiological conditions), that hippocampal circuit overactivity is linked to increased amyloid burden, and by extension, to AD vulnerability. 

    Additionally, let's consider APOE4. Given that APOE4 has been linked to modifications in both synaptic development (Dumanis et al., 2009) and signaling pathways underlying synaptic plasticity (Kim et al., 2014; Segev et al., 2015; Zhu et al., 2015), it is certainly plausible that multiple ways exist by which APOE is acting (even independently of its role in amyloid aggregation) to impact activity in these hippocampal circuits throughout the lifespan. Therefore, this finding provides support for studying the pleiotropic effects of APOE on brain function, and how these effects may relate to AD vulnerability.

    The second study I wanted to comment on was previous work (covered by AlzForum) on place cells in AD. In that study, John O’Keefe (co-awardee of the 2014 Nobel Prize with May-Britt and Edvard Moser) and colleagues demonstrated that place cells activity could be assayed in vivo in AD mouse models (Cacucci et al., 2008), raising the possibility that similar methods could be employed to further examine these proposed grid cell effects using either an AD mouse model or an APOE4 mouse model (e.g., targeted replacement mice).


    . Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7863-8. PubMed.

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    . Apolipoprotein E in synaptic plasticity and Alzheimer's disease: potential cellular and molecular mechanisms. Mol Cells. 2014 Nov;37(11):767-76. Epub 2014 Oct 30 PubMed.

    . PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice. J Neurosci. 2015 Sep 23;35(38):12986-93. PubMed.

    . Chronic optogenetic activation augments aβ pathology in a mouse model of Alzheimer disease. Cell Rep. 2015 May 12;11(6):859-65. Epub 2015 Apr 30 PubMed.

    . Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):11965-70. Epub 2015 Sep 8 PubMed.

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News Citations

  1. Zuers—Can Spatial Navigation Guide Clinical Trials?
  2. Brain Volume, Myelination Different in Infants Carrying ApoE4
  3. Does Brain Development in Childhood Set the Stage for Dementia?

Paper Citations

  1. . The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011 Feb;121(2):171-81. PubMed.
  2. . High frequency of apolipoprotein E epsilon4 allele in young individuals with very mild Alzheimer's disease-related neurofibrillary changes. Exp Neurol. 1998 Sep;153(1):152-5. PubMed.
  3. . Evidence for grid cells in a human memory network. Nature. 2010 Feb 4;463(7281):657-61. Epub 2010 Jan 20 PubMed.
  4. . Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012 Dec;11(12):1048-56. PubMed.
  5. . Detecting navigational deficits in cognitive aging and Alzheimer disease using virtual reality. Neurology. 2008 Sep 16;71(12):888-95. PubMed.
  6. . Spatial navigation measured by the Floor Maze Test in patients with subjective cognitive impairment, mild cognitive impairment, and mild Alzheimer's disease. Int Psychogeriatr. 2015 Aug;27(8):1401-9. Epub 2015 Feb 3 PubMed.

Further Reading


  1. . Place cells, grid cells, and memory. Cold Spring Harb Perspect Biol. 2015 Feb 2;7(2):a021808. PubMed.
  2. . Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: Insights from imaging and behavioral studies. Ageing Res Rev. 2012 Jul 5; PubMed.
  3. . Neural correlates of spatial navigation changes in mild cognitive impairment and Alzheimer's disease. Front Behav Neurosci. 2014;8:89. Epub 2014 Mar 17 PubMed.

Primary Papers

  1. . Reduced grid-cell-like representations in adults at genetic risk for Alzheimer's disease. Science. 2015 Oct 23;350(6259):430-3. PubMed.