Alzheimer’s disease (AD) is associated with cognitive impairments and age-dependent memory deficits which have been studied using genetic models of AD. Whether the processes for modulating memory persistence are more vulnerable to the influence of amyloid pathology than the encoding and consolidation of the memory remains unclear. Here, we investigated whether early amyloid pathology would affect peri-learning novelty in promoting memory, through a process called behavioral tagging and capture (BTC). AppNL-G-F/NL-G-F mice and wild-type littermates were trained in an appetitive delayed matching-to-place (ADMP) task which allows for the assessment of peri-learning novelty in facilitating memory. The results show that novelty enabled intermediate-term memory in wild-type mice, but not in AppNL-G-F/NL-G-F mice in adulthood. This effect preceded spatial memory impairment in the ADMP task seen in middle age. Other memory tests in the Barnes maze, Y-maze, novel object or location recognition tasks remained intact. Together, memory modulation through BTC is impaired before apparent deficits in learning and memory. Relevant biological mechanisms underlying BTC and the implication in AD are discussed.

Background: Prior experience in early life has been shown to improve performance in aging and mice with Alzheimer’s disease (AD) pathology. However, whether cognitive training at a later life stage would benefit subsequent cognition and reduce pathology in AD mice needs to be better understood. Objective: This study aimed to verify if behavioral training in mid-adulthood would improve subsequent cognition and reduce AD pathology and astrogliosis. Methods: Mixed-sex APP/PS1 and wildtype littermate mice received a battery of behavioral training, composed of spontaneous alternation in the Y-maze, novel object recognition and location tasks, and spatial training in the water maze, or handling only at 7 months of age. The impact of AD genotype and prior training on subsequent learning and memory of aforementioned tasks were assessed at 9 months. Results: APP/PS1 mice made more errors than wildtype littermates in the radial-arm water maze (RAWM) task. Prior training prevented this impairment in APP/PS1 mice. Prior training also contributed to better efficiency in finding the escape platform in both APP/PS1 mice and wildtype littermates. Short-term and long-term memory of this RAWM task, of a reversal task, and of a transfer task were comparable among APP/PS1 and wildtype mice, with or without prior training. Amyloid pathology and astrogliosis in the hippocampus were also comparable between the APP/PS1 groups. Conclusion: These data suggest that cognitive training in mid-adulthood improves subsequent accuracy in AD mice and efficiency in all mice in the spatial task. Cognitive training in mid-adulthood provides no clear benefit on memory or on amyloid pathology in midlife.