Differences in retroactive interference response reveal sex-specific memory resilience in pre-symptomatic triple...

Alzheimer's disease is a neurodegenerative disorder characterized by memory loss dependent on hippocampal and parahippocampal cortex dysfunction. However, recent evidence shows that patients with mild cognitive impairment progressing to Alzheimer's disease can exhibit early symptoms when assessed with more nuanced memory tests, such as those evaluating memory vulnerability to interference. Here, we characterize how sex and genotype shape the response to retroactive interference in triple-transgenic Alzheimer's disease mice at an early stage of the phenotype, when overt memory deficits are not yet present. Wild-type females were the only group resisting interference: transgenic females failed to discriminate despite normal recognition memory, irrespective of the moment during which retroactive interference was experienced, and males of both genotypes were similarly impaired at every time point tested. Both context change and increased memory strength restored discrimination in transgenic females and wild-type males, suggesting that their susceptibility depends on overlapping hippocampal representations. Transgenic males, by contrast, remained impaired when interference occurred in a different context and showed only a limited improvement after multiple training, pointing to a larger contribution of interference-induced memory decay. Overall, our data characterize the response to retroactive interference as a sex-dependent behavioural readout of early memory instability in a preclinical model of Alzheimer's disease.