Path integration deficits with phosphorylated tau accumulation in the entorhinal cortex in mice and humans

Background: Alzheimer's disease (AD) is a devastating disease that is accompanied by dementia, and its incidence increases with age. However, no interventions have exhibited clear therapeutic effects. We aimed to develop and characterize behavioral tasks that allow the earlier identification of signs preceding dementia that would facilitate the development of preventative and therapeutic interventions for AD. Method To this end, we developed a 3D virtual reality task sensitive to the activity of grid cells in the entorhinal cortex, which is the region that first exhibits neurofibrillary tangles in AD. We investigated path integration (assessed by error distance) in a spatial navigation task sensitive to grid cells in the entorhinal cortex in 177 volunteers without dementia between 20 and 89 years old. Results In each age group, the percentage of subjects showing impaired path integration correlated with the percentage of subjects showing neurofibrillary tangles in the entorhinal cortex (based on previously published autopsy data) (correlation coefficient = 0.96). To confirm the underlying mechanisms, we investigated a tauopathy mouse model (P301S mutant tau-overexpressing mice; PS19 mice) at 6 months of age, which showed a noticeable accumulation of phosphorylated tau only in the entorhinal cortex, associated with impaired path integration without impairments in spatial cognition or novel object recognition. Conclusion These data suggest that path integration deficit is caused by the accumulation of phosphorylated tau in the entorhinal cortex. This method may allow the early identification of individuals who are likely to develop AD.