Disrupted spatial and contextual memory encoding in the hippocampus of 5xFAD mice precedes cognitive impairment

Alzheimers disease (AD) is characterised by progressive memory decline, yet how hippocampal representations change at early disease stages remains largely unknown. Using a real-world head-fixed spatial alternation task combined with in vivo two-photon imaging, we examined hippocampal CA1 representations in 5xFAD mice. Although 7-12 month old 5xFAD mice exhibited significant impairments in task learning, 2-4 month old mice performed normally, allowing us to assess hippocampal coding before behavioural decline. At this early stage, CA1 neurons showed intact global spatial encoding but impaired task-related place cell representations. Contextual representations revealed by trajectory-dependent coding were weakened at both the population and single cell levels, accompanied by a shift from predominantly retrospective towards more prospective encoding along the central arm. Despite these vulnerabilities, a subset of place cells largely retained stable spatial representations that persisted throughout task learning in early-stage AD mice. Chemogenetic activation of basal forebrain cholinergic neurons improved spatial information rates and stability of spatial and contextual coding in early-stage 5xFAD mice. Together, these findings show that hippocampal spatial and contextual coding is disrupted early in AD, while a subset of stable place cells remains preserved, and that these representational deficits emerge before impairments in spatial alternation behaviour.