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.