In order to understand the long-term effects of systemic inflammation, it is important to distinguish inflammation-induced changes in baseline cognitive function from changes that interact with aging to influence the trajectory of cognitive decline. Lipopolysaccharide (LPS; 1 mg/kg) or vehicle was administered to young adult (6 months) male rats via intraperitoneal injections, once a week for 7 weeks. Longitudinal effects on cognitive decline were examined 6 and 12 months after the initial injections. Repeated LPS treatment, in adults, resulted in a long-term impairment in memory, examined in aged animals (age 18 months), but not in middle-age (age 12 months). At 12 months following injections, LPS treatment was associated with a decrease in N-methyl-D-aspartate receptor-mediated component of synaptic transmission and altered expression of genes linked to the synapse and to regulation of the response to inflammatory signals. The results of the current study suggest that the history of systemic inflammation is one component of environmental factors that contribute to the resilience or susceptibility to age-related brain changes and associated trajectory of cognitive decline.