Soluble amyloid-beta (Aβ) deposition, a hallmark of Alzheimer's Disease (AD), manifests in the brain well before clinical symptoms arise, correlating with cognitive decline. This correlation underscores the necessity for early detection biomarkers for Aβ accumulation, providing a window to identify at-risk individuals during the preclinical stage of AD. Supporting this, research has demonstrated that individuals with a genetic predisposition for AD exhibit deficits in path integration (PI)—the ability to track one's position in space without visual cues. Functional MRI studies have further implicated these PI deficits to a compromised grid cell network within the medial entorhinal cortex (MEC), indicating that grid cells play a crucial role in the cognitive deterioration seen in early AD stages. To further elucidate the connection between grid cell dysfunction and PI deficits during initial Aβ pathology, our research has delved into the spatial memory systems in the J20 transgenic mouse model, which simulates amyloidosis. Our findings reveal significant impairments in both grid cell activity and path integration behaviors in these Alzheimer's disease models at pre-symptomatic stages (Ying et al., 2022 Nature Communications; Ying et al., 2023 Current Biology). These insights have propelled our ongoing development of advanced, scalable path integration assays designed to detect early-stage Alzheimer’s and to assess therapeutic interventions in both murine models and human subjects, as detailed in our comprehensive review (Vladislava, Ying, et al., 2021, Trends in Cognitive Sciences). These concerted efforts aim to bridge the gap between molecular pathology and cognitive symptoms of AD, enhancing our understanding of the disease’s early impact on navigation-related brain circuits.