Tau pathology is associated with postsynaptic metabotropic glutamate receptor 5 (mGluR5) in early Alzheimer's disease in a sex‐specific manner

Abstract INTRODUCTION To investigate the associations of metabotropic glutamate receptor 5 (mGluR5) with tau deposition and cognitive ability in patients with early Alzheimer's disease (AD). METHODS Twenty‐six cognitively impaired (CI) and 14 cognitively unimpaired (CU) individuals underwent mGluR5 positron emission tomography (PET) ([ 18 F]PSS232), amyloid PET ([ 18 F]florbetapir), and tau PET ([ 18 F]MK6240), and neuropsychological assessment. The relationships among mGluR5 availability, tau deposition, and neuropsychological assessment were analyzed using Spearman's correlation and mediation analyses. RESULTS CI patients had lower mGluR5 in the hippocampus than CU (standardized uptake value ratio [SUVr]: 2.03 ± 0.25 vs 1.79 ± 0.17, p = 0.003). Hippocampal mGluR5 was negatively associated with hippocampal tau deposition ( r = −.46, p = 0.003) and positively associated with cognitive performance, but only in women. Hippocampal tau deposition mediated the effect of mGluR5 on cognitive performance. DISCUSSION Reduced hippocampal mGluR5 is negatively related with tau deposition in most cortical regions and positively associated with cognitive performance, making it a promising biomarker for AD diagnosis and therapy. Highlights Cognitively impaired (CI) patients exhibited lower metabotropic glutamate receptor 5 (mGluR5) availability in the hippocampus than cognitively unimpaired (CU) subjects. Hippocampal mGluR5 availability was negatively associated with tau deposition in widespread cortex. Hippocampal mGluR5 availability was positively associated with cognitive performance. The close association of mGluR5 with tau and cognition performance exists only in females. Tau pathology mediated the relationship between mGluR5 availability and cognition.