Impaired Parahippocampal Gyrus-Orbitofrontal Cortex Circuit Associated with Visuospatial Memory Deficit as a Potential Biomarker and Interventional Approach for Alzheimer Disease.

The parahippocampal gyrus-orbitofrontal cortex (PHG-OFC) circuit in humans is homologous to the postrhinal cortex (POR)-ventral lateral orbitofrontal cortex (vlOFC) circuit in rodents. Both are associated with visuospatial malfunctions in Alzheimer's disease (AD). However, the underlying mechanisms remain to be elucidated. In this study, we explored the relationship between an impaired POR-vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice, and investigated alterations of the PHG-OFC circuit by multi-domain magnetic resonance imaging (MRI) in patients on the AD spectrum. We demonstrated that an impaired glutamatergic POR-vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice. Moreover, MRI measurements of the PHG-OFC circuit had an accuracy of 77.33% for the classification of amnestic mild cognitive impairment converters versus non-converters. Thus, the PHG-OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD, thereby providing a potential predictor for AD progression and a promising interventional approach for AD.