Alzheimer's disease is characterized by a loss of cognitive function that is caused by the death of neurons in the brain. This cell death is likely due, in part, to the toxic effects of aggregates of a small peptide, amyloid-beta, which eventually accumulates into dense plaques scattered throughout the brain. Recent work has shown local damage to neurons as well as locally increased inflammation near these plaques, suggesting that the plaques create a toxic microenvironment that could affect many functions. In addition, recent clinical research in humans and experimental work in animals suggest that blood flow to the brain is impaired in Alzheimer's disease. We propose to test the idea that this blood flow impairment is not due to a modest reduction in blood flow in all vessels in the brain, but rather due to an effect that is localized near the amyloid plaques, where blood vessels near plaques are dramatically slowed or clotted while vessels far from plaques are unaffected. These localized blood flow reductions could exacerbate damage to local brain cells by depriving them of oxygen and nutrients and could potentially accelerate the formation of new amyloid plaques, leading to a vicious cycle of damage to the brain. Using advanced optical imaging techniques together with transgenic mice that develop Alzheimer's disease, we will study whether the blood flow reduction in the brain that occurs with Alzheimer's disease is due to preferential slowing or increased clotting of vessels near amyloid plaques. Our work will further test whether these local blood flow reductions are due to inflammation, clotting, or damage due to free radicals, thereby identifying potential targets for the future development of therapeutic strategies. The cumulative effect of many of these blood flow disruptions, essentially small strokes, could contribute significantly to the neuronal damage and cognitive decline seen in Alzheimer's disease. The treatment strategies one would devise for these small strokes may be very different from those for a more uniform reduction in blood flow to the brain, so it is essential to determine whether or not there are local effects of amyloid plaques on cortical blood flow and what disease pathways are involved.