Alzheimer's Disease (AD), responsible for the majority of dementia cases, is a progressive neurodegenerative disorder marked by amyloid-β accumulation, tauopathy, neuroinflammation, and cognitive decline. Parallel to this cognitive decline, the number of memory-related neurons (engram cells) is reduced in the APPswe/PSEN1dE9 mouse model for slow-progressing AD, crossed with a genetically modified mouse line that allows us to visualize engram neurons (Arc::dVenus mice). We hypothesize that aberrant microglial modulation of engram cells might contribute to the AD-related changes in engram and cognitive decline.Contextual fear conditioning (3 x 0.65 mA foot shock) was employed to activate fear memory-associated neurons, which would then express the destabilized Venus (dVenus) fluorophore under the Arc promoter. Engram cells (via antibodies against GFP to amplify dVenus+ signal), microglia (Iba1) and microglial phagocytosis (CD68) were detected via immunofluorescence. Engram size was quantified by counting number of GFP+ neurons. At 9 months of age, APPswe/PSEN1dE9 mice displayed reduced freezing levels during the contextual fear test. Measurements of microglial morphology and CD68 expression in the engram microenvironment, the number of GFP+ puncta in Iba1+ microglia, and the connections of the microglia with the engram neurons are currently ongoing to assess microglial modulation of the engram neurons.We expect elevated CD68 and dVenus+ puncta in AD mouse microglia, indicating potential microglial involvement in synaptic pruning from engram neurons and its potential association with memory deficits. This project will provide insights into microglial modulation of engram neurons and their potential contribution to AD-related memory deficits.