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Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

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INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.



Alzheimer's disease, entorhinal cortex, path integration, preclinical, virtual reality

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Alzheimers Dement

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Wellcome Trust (098436/Z/12/B)
Wellcome Trust (Unknown)
Merck Investigator Studies Program grant MISP-57175 (DC) Alzheimer's Society grants 178, 264 and 397 (DC, CN, PREVENT Dementia) UK National Institute for Health Research Clinical Research Network and Biomedical Research Centre Cambridge grant 1215-20014 (PREVENT Dementia, JOB), Oxford (IK), Imperial (PM) US Alzheimer's Association grant TriBEKa-17–519007 (PREVENT Dementia) Alzheimer’s Research UK (DC, LS) Wellcome grant 098436/Z/12/B (CTR), grant 202805/Z/16/Z; (NB, AC) UK Medical Research Council grant SUAG/046 G101400 (RH), Dementia’s Platform UK grant (IK) National Institute of Neurological Disorders and Stroke of the National Institutes of Health grant K99NS126715 (MS)