Newly published research reveals Alzheimer’s impact on the brain’s spatial navigation system

May 22, 2023

Successful navigation requires information about the external world and our perception of body movement (also referred to as self-motion cues which include vestibular feedback, proprioception, and optic flow). A recent study from Dr. Mark P. Brandon’s Lab investigated a mouse model of Alzheimer’s disease and found that prior to the expression of amyloid-beta plaques (a hallmark of late-stage pathology), grid cells in Alzheimer’s disease mice exhibited numerous coding impairments related to the animal’s inability to integrate self-motion cues. These findings suggest that spatial navigation deficits in early Alzheimer’s disease patients arise due to difficulty in processing information about one’s movement in space rather than the outside world itself. The article, entitled “Grid cell disruption reflects reduced integration of self-motion cues in an early Alzheimer’s disease mouse model,” was published this week in Current Biology.

As we navigate the world, grid cells in a brain region called the medial entorhinal cortex fire in multiple spatial locations that form a periodic hexagonal array which tiles the entirety of space, akin to an internal GPS system.

Our research helps clarify this internal coordinate system’s disruption in early Alzheimer’s pathology.
– Dr. Mark Brandon, Researcher at the Douglas Research Centre, Associate Professor at McGill University and corresponding researcher of the study.

The periodic spatial code provides an internal positional coordinate system that helps us navigate. A previous study from Dr. Brandon’s lab showed that grid cells were disrupted during the early stages of pathology in an Alzheimer’s disease mouse model, providing the first evidence to suggest that grid cells may underlie spatial navigation deficits commonly reported in preclinical individuals.

However, do these early navigation deficits arise because the individual cannot accurately perceive information about either the external world or their own movement in space? Grid cells offer a unique opportunity to answer this question from a cellular level because environmental information and self-motion cues both constitute necessary input sources that maintain regular grid cell firing.

This follow-up study led by PhD student Johnson Ying aimed to determine if disrupted grid cell firing during early Alzheimer’s disease pathology is attributable to reduced integration of self-motion cues or environmental information.

The authors show that grid cell firing was spatially unstable when Alzheimer’s disease mice wandered towards the square arena’s center – a region where the sparsity of environmental landmarks requires the animal to rely on self-motion to maintain its sense of location.

These observations highlight how a disruption in integrating self-motion cues could signify early Alzheimer’s.
– Dr. Mark Brandon

In contrast, grid cell firing was normal when Alzheimer’s disease mice navigated close to the borders which act as salient landmarks that anchor the animal to their surroundings. Unstable grid cell activity towards the center but not the borders strongly suggests that Alzheimer’s disease mice could not effectively integrate self-motion cues.

A deeper analysis revealed that the grid cell spatial code in Alzheimer’s disease mice was no longer purely hexagonal but adopted a square-like structure resembling the arena’s geometrical layout. In other words, Alzheimer’s disease grid cells appeared to rely more on features of the external world rather than self-motion cues. How might this be detrimental to navigation performance during early Alzheimer’s disease? Hexagonal structure is superior to square-like structure in terms of angular resolution and sampling frequency between vertices. During navigation, 60° vertices allow for more frequent updating of heading direction, as well as spatial displacement between intersection points.

There is no cure for Alzheimer’s disease, in part because therapeutics are administered too late. The failure of multiple Alzheimer’s disease clinical trials highlights the need for markers that identify individuals at early risk. In the last decade, spatial navigation deficits have emerged as one of the most sensitive behavioural markers of early Alzheimer’s disease.

These findings support the potential of spatial navigation tasks for early Alzheimer’s detection. They underline the need for specialized tasks that focus on self-motion cues, offering hope for the understanding of early Alzheimer’s mechanisms.
– Dr. Mark Brandon

The findings of this study not only further justify the implementation of spatial navigation tasks in the clinic as a sensitive behavioural marker of early Alzheimer’s disease, but specifically highlight the need for specialized spatial tasks that examine the patient’s ability to navigate by relying only on self-motion cues.

Read the full article here: Ying J, Reboreda A, Yoshida M, Brandon MP. Grid cell disruption in a mouse model of early Alzheimer’s disease reflects reduced integration of self-motion cues. Current Biology.Published: May 22, 2023