Hippocampal lesions are a defining pathology of Alzheimer’s disease (AD). However, the molecular mechanisms that underlie hippocampal synaptic injury in AD have not been fully elucidated. Current therapeutic efforts for AD treatment are not effective in correcting hippocampal synaptic deficits. Growth hormone secretagogue receptor 1α (GHSR1α) is critical for hippocampal synaptic physiology. Here, we report that GHSR1α interaction with β-amyloid (Aβ) suppresses GHSR1α activation, leading to compromised GHSR1α regulation of dopamine receptor D1 (DRD1) in the hippocampus from patients with AD. The simultaneous application of the selective GHSR1α agonist MK0677 with the selective DRD1 agonist SKF81297 rescued Ghsr1α function from Aβ inhibition, mitigating hippocampal synaptic injury and improving spatial memory in an AD mouse model. Our data reveal a mechanism of hippocampal vulnerability in AD and suggest that a combined activation of GHSR1α and DRD1 may be a promising approach for treating AD.