This study tested anti-inflammatory drug minocycline on Aβ levels, microglia and astrocyte activation, and behavioral cognition in an AD mouse model. Past studies have shown activated microglia and astrocytes neuroinflammation are associated with Aβ deposits and cognitive decline in Alzheimer's disease. Results from this study showed after intraperitoneal injection every other day for four weeks in twelve-month old Tg-SwDI mice, minocycline treatment had no effect on cerebral Aβ accumulation, microvascular amyloid load, or soluble oligomeric Aβ levels. Although reactive astrocyte levels were unaffected, there was a significant reduction in the numbers of activated microglial cells, reduced levels of proinflammatory IL-6, and improved performance in spatial learning memory. These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Aβ.