AbstractBackgroundMemories must be accessible for them to be useful. Alzheimer’s disease (AD) is a progressive form of dementia in which cognitive capacities slowly deteriorate due to underlying neurodegeneration. Interestingly, anecdotal observations have demonstrated that Alzheimer’s patients can exhibit cognitive fluctuations during all stages of the disease. In particular, it is thought that contextual factors are critical for unlocking these hidden memories. To date, however, exploration of the neural basis of cognitive fluctuations has been hampered due to the lack of a behavioral approach in mouse models to dissociate memories from contextual performance.MethodOur previous work demonstrated that interleaving ‘reinforced’ trials with trials without reinforcement (‘probe’ trials) in an auditory go/no‐go discrimination task, allows us to distinguish between acquired sensorimotor memories and their contextual expression. Here, we used this approach, together with two‐photon calcium imaging on behaving AD‐relevant mice (APP/PS1+), to determine whether amyloid accumulation impacts underlying sensorimotor memories (measured using ‘probe’ trials) and/or contextual‐performance (measured using ‘reinforced’ trials) in an age dependent manner.ResultImportantly, peripheral auditory function, measured using the threshold for detecting an auditory brainstem response, was similar between WT and APP/PS1+ mice. We found that while contextual‐performance is significantly impaired in young adult APP/PS1+ mice compared to age‐matched controls, these animals show only minor impairments in the underlying sensorimotor memories. However, middle aged APP/PS1+ mice show deficits in both domains. The impairment found in the young adults was accompanied by a reduction in stimulus selectivity and behavioral encoding in the auditory cortex of APP/PS1+ mice that that can be partially restored in probe trials. Ongoing analyses aim to identify whether this impairment is cortex‐wide or is concentrated near Aβ plaques. Finally, these effects were recapitulated by using a reinforcement learning model that accounts for changes in contextual signals. The main network model parameters affected between the control and the APP/PS1+ mice were those governing contextual scaling and behavioral inhibition.ConclusionThese results suggest that Aβ deposition impacts circuits involved in contextual computations before those involved in acquiring knowledge and that neural circuit interventions, such as modulating inhibition, may hold promise to reveal hidden memories.