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The 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, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours.Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231173587 for Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife by Maria-Eleni Dounavi, Elijah Mak, Peter Swann, Audrey Low, Graciela Muniz-Terrera, Anna McKeever, Marianna Pope, Guy B Williams, Katie Wells, Brian Lawlor, Lorina Naci, Paresh Malhotra, Clare Mackay, Ivan Koychev, Karen Ritchie, Li Su, Craig W Ritchie and John T O’Brien: on behalf of the SVDs@target consortium in Journal of Cerebral Blood Flow & Metabolism

The 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, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains., Competing Interests: Competing interests: The authors declare that they have no competing interests.