(300 WORDS MAX)Cerebral blood flow decreases of about 30% have been noted in both humans with Alzheimer's disease (AD) as well as in mouse models of AD, and may play a role in cognitive impairment. The underlying mechanism for this decrease in cerebral blood flow has not yet been elucidated. In recent work, we have discovered that there is an approximately six-fold elevation, from 0.3 % to 1.8%, in the number of brain capillaries that are stalled in aged AD mice as compared to age-matched controls. In previous work, we also quantified the downstream blood flow decreases that result from the occlusion of a single cortical capillary. Based on this data, we predict that the increase in capillary stalls we have observed in AD mice would lead to an overall 30% decrease in cerebral perfusion, suggesting that the decreased cerebral blood flow in AD could be caused by stalled flow in brain capillaries. In preliminary data, we have further linked these stalls to leukocytes that are firmly adhered to the endothelium of capillaries. Many studies have noted an increase in inflammation in the AD brain, which could cause activation of endothelial cells and lead to such leukocyte plugging. Here, we propose to build on our preliminary data and confirm that leukocyte plugging causes the increased stalling of brain capillaries in AD mice. We then will block the interaction between leukocytes and inflamed endothelial cells using blocking antibodies and determine if this resolves the capillary stalls and leads to increased cerebral perfusion. Taken together, this work would definitively identify leukocyte plugging as a cause for the decreased brain blood flow seen in AD as well as determine how much cerebral blood flow could be increased by eliminating the leukocyte plugs, suggesting a novel therapeutic target for AD.