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

Navigation processes mediated selectively by the entorhinal cortex (EC) may be impaired in individuals with suspected preclinical Alzheimers 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 AD-related 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.