Amyloid-related longitudinal postsynaptic decline in Alzheimer's disease

<title>Abstract</title> <p> Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, tau neurofibrillary tangles, and synaptic dysfunction. Cellular prion protein mediates Aβ oligomer neurotoxicity through metabotropic glutamate receptor 5 (mGluR5), leading to synaptic impairment and loss. However, the longitudinal trajectory of mGluR5 and its relationship with amyloid pathology remain poorly understood in vivo. We performed baseline dual-tracer PET imaging in 38 participants and longitudinal [ ¹⁸ F] PSS232PET/MR in 23 cognitively impaired patients over a mean follow-up of 14.3 months. Longitudinal analyses revealed widespread reductions in mGluR5 availability among Aβ-positive individuals, whereas Aβ-negative participants exhibited more restricted declines. Baseline amyloid pathology predicted accelerated mGluR5 decline in parahippocampus and hippocampus. Higher baseline hippocampal mGluR5 availability was associated with accelerated subsequent cognitive decline, suggesting that preserved or compensatorily elevated mGluR5 may identify individuals at increased risk of future deterioration. These findings indicate that longitudinal mGluR5 decline follows an amyloid-dependent spatiotemporal pattern, with selective medial temporal vulnerability in Aβ-positive individuals. This study provides in vivo evidence linking amyloid pathology to progressive mGluR5 dysfunction and supports the development of mGluR5-targeted therapeutic strategies for amyloid-positive AD. </p>