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Entorhinal cortex is affected early in Alzheimer’s disease and is critical for navigation. Using immersive virtual reality, Howett et al. reveal navigational deficits in biomarker-positive patients with mild cognitive impairment. Navigational deficits are more sensitive and specific to Alzheimer’s disease risk than a battery of reference cognitive tests.
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 (PI), we predicted that PI impairment would represent the first behavioural change in adults at risk of AD. Using immersive VR, we found that midlife PI 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 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.
Pathological changes in the medial temporal lobe (MTL) are found in the early stages of Alzheimer's disease (AD) and aging. The earliest pathological accumulation of tau colocalizes with the areas of the MTL involved in object processing as part of a wider anterolateral network. Here, we sought to assess the diagnostic potential of memory for object locations in iVR environments in individuals at high risk of AD dementia (amnestic mild cognitive impairment [aMCI] n = 23) as compared to age‐related cognitive decline. Consistent with our primary hypothesis that early AD would be associated with impaired object location, aMCI patients exhibited impaired spatial feature binding. Compared to both older (n = 24) and younger (n = 53) controls, aMCI patients, recalled object locations with significantly less accuracy (p < .001), with a trend toward an impaired identification of the object's correct context (p = .05). Importantly, these findings were not explained by deficits in object recognition (p = .6). These deficits differentiated aMCI from controls with greater accuracy (AUC = 0.89) than the standard neuropsychological tests. Within the aMCI group, 16 had CSF biomarkers indicative of their likely AD status (MCI+ n = 9 vs. MCI− n = 7). MCI+ showed lower accuracy in the object‐context association than MCI− (p = .03) suggesting a selective deficit in object‐context binding postulated to be associated with anterior‐temporal areas. MRI volumetric analysis across healthy older participants and aMCI revealed that test performance positively correlates with lateral entorhinal cortex volumes (p < .05) and hippocampus volumes (p < .01), consistent with their hypothesized role in binding contextual and spatial information with object identity. Our results indicate that tests relying on the anterolateral object processing stream, and in particular requiring successful binding of an object with spatial information, may aid detection of pre‐dementia AD due to the underlying early spread of tau pathology.
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