Unmasking selective path integration deficits in Alzheimer’s disease risk carriers

Abstract

Alzheimer’s disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOE ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE ε4-carriers during a virtual navigation task. We report a selective impairment in APOE ε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations when no compensatory strategies were available, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ε4-carriers. Furthermore, posterior cingulate/retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset.

Memory precision of object-location binding is unimpaired in APOE ε4-carriers with spatial navigation deficits

“…This very specific impairment is thought to be a result of early tau pathology in the ERC thought to alter the integrity of grid cell representations, which are essential for updating self-motion during navigation. 9,72,[109][110][111] This interpretation is in line with recent evidence suggesting that preclinical ε4-carriers only exhibit spatial navigation deficits in the absence of nearby landmarks or environmental boundaries that normally correct for accumulating temporal error in the grid-cell code. 110,112 Although grid cells are most famously involved in spatial navigation, they also support visual memory.…”

“…9,72,[109][110][111] This interpretation is in line with recent evidence suggesting that preclinical ε4-carriers only exhibit spatial navigation deficits in the absence of nearby landmarks or environmental boundaries that normally correct for accumulating temporal error in the grid-cell code. 110,112 Although grid cells are most famously involved in spatial navigation, they also support visual memory. 113 Research suggests that both visual and navigational processes are supported by the entorhinal cortex via common mechanisms that include the formation of spatial or visual maps via grid cells.…”

“…115 It may therefore be surprising that we did not find any effect in our relational memory precision task, while impairments were observed in the navigation task by Coughlan et al 9 However, the border bias is a very specific behaviour in ε4-carriers that appears when arenas have larger open spaces where anchoring spatial maps to nearby landmarks cannot be used as a corrective strategy. 9,72,110 Therefore, it has no direct equivalent in 2D visual scene memory in our precision task. This may explain why there is an effect of the ε4-allele on virtual reality spatial navigation but not in object-location memory precision in our sample.…”

“…This subtle navigational deficit was attributed to a bias toward navigating close to environmental boundaries, as previously documented in an independent cohort (Kunz et al ., 2015). This very specific impairment may be a result of early tau pathology in the ERC thought to alter the integrity of grid cell representations, which are essential for updating self-motion during navigation (Lithfous et al ., 2013; Kunz et al ., 2015; Coughlan et al ., 2019; Bierbrauer et al ., 2020; Levine et al ., 2020). This interpretation is in line with recent evidence suggesting that preclinical ε4-carriers only exhibit spatial navigation deficits in the absence of nearby landmarks or environmental boundaries that normally correct for accumulating temporal error in the grid-cell code (Hardcastle et al ., 2015; Bierbrauer et al ., 2020).…”

Reframing spatial frames of reference: What can aging tell us about egocentric and allocentric navigation?

“…With the advent of virtual reality technology, these spaces are designed more and more as arenas in which individuals see the environment from their own first‐person perspective on a computer screen (Figure 2). Specifically, many studies that aim to capture this memory representation often rely on testing path integration , or dead reckoning, wherein participants need to keep track of a starting location in relation to their own position in space (Bierbrauer et al, 2020; Byrne, Becker, & Burgess, 2007). This tracking, in turn, relies on the integration of multimodal sensory cues generated both from self‐motion and the surrounding environment, referred to respectively as idiothetic and allothetic spatial cues.…”