Age-dependent vulnerability to spatial memory interference in APP/PS1 mice.

Background: While Alzheimer's disease (AD) is well known for progressive memory impairment, less is understood about how amyloid pathology affects flexible updating of competing spatial representations. Here, we used the Objects in Updated Locations (OUL) paradigm to investigate how amyloidosis influences spatial memory updating and the handling of competing mnemonic information in APP/PS1 mice. Methods: APP/PS1 and wild-type control mice were tested in the OUL paradigm, which probes memory for object displacement and subsequent updating of overlapping spatial representations. Exploration behavior was quantified using an automated behavioral tracking pipeline based on object proximity and gaze orientation criteria and validated against blinded manual scoring. Object discrimination performance was assessed during the object displacement session and during the subsequent updating performance session involving competing spatial information. cFos immunohistochemistry following novelty exposure was used to assess neuronal recruitment associated with memory performance. Results: During the object displacement session, control mice reliably discriminated the displaced object location, whereas APP/PS1 mice showed weaker and more variable performance, with a greater proportion failing to reach discrimination criterion levels. During the subsequent updating performance session, control mice demonstrated more flexible adaptation across overlapping spatial representations, while APP/PS1 mice exhibited weaker performance under conditions involving competing spatial traces. In APP/PS1 mice, longer exploration latencies were negatively associated with discrimination performance specifically under competing-memory conditions. Age-stratified analyses revealed a significant genotype effect in older animals, driven primarily by the condition involving overlapping spatial representations. In control mice, cFos expression in hippocampal regions associated with spatial memory processing correlated with behavioral performance, whereas these relationships were absent in APP/PS1 mice. Conclusion: These findings indicate that amyloidosis is associated with reduced reliability of spatial memory performance and impaired handling of competing spatial information, particularly under conditions requiring flexible updating of overlapping mnemonic representations. The results further suggest increased vulnerability to interference-related spatial memory deficits with age. Together, these findings support the utility of the OUL paradigm for studying memory updating impairments in AD-related pathology and identify flexible spatial updating under interference as a sensitive behavioral domain affected by amyloidosis.