Functional connectivity between the entorhinal and posterior cingulate cortices associated with navigation impairment following path integration in at-genetic-risk Alzheimer’s disease

Abstract

count: Main text count: Tables: Figures: Abbreviations: AD = Alzheimer's disease; VST = Virtual Supermarket task, APOE = Apolipoprotein Epsilon; EC = Entorhinal Cortex; MCI = Mild Cognitive Impairment; PCC = Posterior Cingulate CortexABSTRACT Navigation processes mediated selectively by the entorhinal cortex (EC) may be impaired in individuals with suspected preclinical Alzheimer's disease (AD), but the clinical utility of navigation tests to detect such impairments remains to be established. In a sample of 64 individuals (32 e3e3 and 32 e3e4), we tested whether an existing paradigm, the Virtual Supermarket Test (VST), can reliably detect the presence or absence of the APOE e4 allele which accelerates amyloid plaque deposition in the brain. The present study assessed four major navigational processes that are subserved by functionally specialised cell groups located in AD vulnerable regions including the EC and examined the relationship between navigation process and regional functional connectivity (FC) given FC is a marker early ADrelated tau seeding. While heading direction and spatial memory were unaffected by at-risk AD, clear altered navigational strategies following path integration were found on the VST in the e3e4 group. The APOE-sensitive VST measure correctly classified 77% of the APOE cohort. Including resting-state FC between the EC and the posterior cingulate cortex, a correlate of the path integration deficit in the APOE e4 group, the classification model increased the accuracy to 85%. Our findings show that at-genetic-risk AD selectively impairs path integration and biases self-reported spatial locations away from the centre and towards the boundary of a virtual environment. Importantly, this impairment is associated with reduced FC between the EC and the posterior cingulate cortex, which in turn informs the neurobiological mechanisms of at-genetic-risk of AD.

Test-retest reliability of spatial navigation in adults at-risk of Alzheimer’s disease

“…While at T1, a paper version of the supermarket map was used to record responses, an alternative form of the VST was employed 18 months later at T2, to facilitate electronic and automatic recording of participant responses on a 9.7inch iPad. VST trials (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) in both versions were identical. At T2, the scoring parameter for VST allocentric memory was updated to include the exact distance of error (here referred to as map drop error), with the specific aim of increasing the sensitivity of the VST sub-measure to measure spatial memory impairment.…”

“…Subsequently, we did not expect this variable to demonstrate test-retest reliability in the normal range. For a visual representation of the task, please see Coughlan et al [ 10 ] Fig 1 : https://www.sciencedirect.com/science/article/abs/pii/S0197458020300348…”

“…Novel spatial navigation measures, the Virtual Supermarket Task (VST) and Sea Hero Quest (SHQ) identify cognitive changes due to functional neural abnormalities within the spatial navigation network (particularly the entorhinal cortex and hippocampus) in at-geneticrisk AD, making them sensitive and specific measures for preclinical AD disease [2,[9][10][11]. Until now however, spatial navigation studies have overlooked the need to establish the testretest reliability of these measures in preclinical AD populations, opting to focus on cross-sectional group comparisons or self-report scales [12], with one exception [13].…”

“…Finally, we examined if the apolipoprotein (APOE) ε4 sensitive navigation parameters predict change in subjective cognitive concerns or neuropsychological performance at retest. In particular, subjective cognitive concerns are typically used characterise preclinical AD [26] The baseline findings for this study are published elsewhere [9,10].…”

Vestibular contribution to path integration deficits in ‘at-genetic-risk’ for Alzheimer’s disease

“…APOE ε2 carriers (15% of the UK population) were also excluded as it is unclear how the ε2 allele acts on cognitive performance or the further development of AD. The sample size required for the present study was determined based on similar studies [20][21][22][23].…”