When you wake up in the morning and head over to the lab, do you take the scenic route and relish in the San Diego sun, or do you take the shortcut through the library because your cat made you late because he craved attention? Memory experts like Dr. Véronique Bohbot at McGill University have begun using virtual and real environments to probe the distinct navigation strategies recruited by your brain when, for example, you orient yourself within a mental map through your morning commute. These navigation strategies are often conjured spontaneously to adapt to the current environment, such as a closed crosswalk, and vary in the amount of localized brain activity evoked in an individual, which in turn depends heavily on the grey matter volume of those specific areas, hormones, and genetic background. However, when someone’s healthy brain fails to employ optimal navigation strategies, they might only experience the mild inconvenience of being late by a few minutes, a sharp contrast to the underlying protracted spatial memory dysfunction found in Alzheimer’s Disease (AD) patients.

Long-term spatial memory impairments are found early in the development of AD, when diagnostic genotyping often reveals the presence of Apolipoprotein E (APOE), a prominent risk gene associated with the disease. A particular APOE allele, ε4, has considerable ties to the cognitive impairments and hippocampal atrophy associated with aging. Interestingly, a different allele, ε2, is known to be protective against AD neuropsychological symptoms, such as cognitive decline and neuritic plaque formation. However, most of these findings have come as a result of studies on older adults with AD onset or progression, and despite the contrast between the structural, protective or risk increasing qualities of the two alleles, it was Dr. Bohbot’s group who recently proposed that cognitive correlates are sensitive to the genotypes even in young adults.

Lesion studies support the idea that different strategies employed while navigating an environment rely on divergent brain networks. For example, the hippocampus-dependent spatial strategy involves creating relationships between the different landmarks in the environment to incorporate into a cognitive map. On the other hand, the caudate-dependent response strategy incorporates stimulus-response associations to orient yourself in space (“take a left after the second right”). In addition, the neuroanatomical basis for these two different spatial strategies also have a structural inverse relationship, such that greater gray matter volume in one correlates with less gray matter volume in the other, and vice versa. Konishi et al. (2016) used this converging evidence to assess whether recruitment of these strategies would relate to the structural differences found between young adult APOE allele carriers, hypothesizing that APOE ε2 carriers will utilize spatial strategies more, and in turn have greater gray matter volume in the hippocampus, in comparison to ε3/ε3 and ε4 allele carriers.

To test this hypothesis, genotyped participants underwent testing in a computer-based virtual reality navigation task that is akin to the eight-arm radial maze, except with landmarks more common to human environments. A subsequent verbal report of the navigation strategy they employed (i.e. “I used landmarks” vs “I used the patter of open pathways”) allowed the researchers to classify participants between spatial and response learners. Follow-up structural Magnetic Resonance Imaging (MRI) on the participants measured hippocampal structural differences between allele carriers and their most utilized navigation strategy.


Schematic drawings and first person views of the 4-on-8 virtual maze


Interestingly, their hypothesis was a home-run. A higher proportion of ε2 allele participants reported using the hippocampus-dependent spatial strategy throughout the task compared to the other allele carriers.



Apoliprotein E (APOE) e2 carriers used the hippocampus-dependent spatial strategy more than the other genotype groups.


In addition, ε2 allele carriers had greater grey matter in the hippocampus compared to both ε3/ ε3 and ε4 carriers. However, these measurements were conducted only in a subset of the 100+ participant pool from the behavioral task. Despite this, these results aligned with previously published studies looking at hippocampal structure in ε2 allele carriers.


Gray matter contrast of APOE e2 carriers and non-e2 carriers using voxel-based morphometry (VBM)


While the ε4 APOE allele has garnered the most attention due to its association with increased risk for AD onset, pursuing assessments on what makes young ε2 allele carriers cognitively distinct from the others can lead to the creation of early intervention strategies. For example, this particular study implies a future clinical scenario where training ε4 carriers to use spatial navigation strategies might mitigate the spatial learning impairments seen throughout AD progression.

Come check out Dr. Bohbot’s talk, titled “Early detection, sex differences, and intervention in healthy older adults at risk of Alzheimer’s disease”, on Tuesday, November 11th, at 4 P.M. in the CNCB  Marilyn Farquhar Seminar Room.

Christian Cazares is a first-year neuroscience graduate student in the Gremel Lab, where he is looking at the effects of stress on goal-directed and habitual behavior. He can be reached at @fleabrained and www.chriscaz.com

Konishi K, Bhat V, Banner H, Poirier J, Joober R, Bohbot VD. APOE2 Is Associated with Spatial Navigational Strategies and Increased Gray Matter in the Hippocampus. Frontiers in Human Neuroscience. 2016;10:349. doi:10.3389/fnhum.2016.00349.


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