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Although immunization against amyloid-␤ (A␤) holds promise as a disease-modifying therapy for Alzheimer disease (AD), it is associated with an undesirable accumulation of amyloid in the cerebrovasculature [i.e., cerebral amyloid angiopathy (CAA)] and a heightened risk of micro-hemorrhages. The central and peripheral mechanisms postulated to modulate amyloid with anti-A␤ immunotherapy remain largely elusive. Here, we compared the effects of prolonged intracerebroventricular (icv) versus systemic delivery of anti-A␤ antibodies on the behavioral and pathological changes in an aged Tg2576 mouse model of AD. Prolonged icv infusions of anti-A␤ antibodies dose-dependently reduced the parenchymal plaque burden, astrogliosis, and dystrophic neurites at doses 10-to 50-fold lower than used with systemic delivery of the same antibody. Both icv and systemic anti-A␤ antibodies reversed the behavioral impairment in contextual fear conditioning. More importantly, unlike systemically delivered anti-A␤ antibodies that aggravated vascular pathology, icv-infused antibodies globally reduced CAA and associated micro-hemorrhages. We present data suggesting that the divergent effects of icv-delivered anti-A␤ antibodies result from gradually engaging the local (i.e., central) mechanisms for amyloid clearance, distinct from the mechanisms engaged by high doses of anti-A␤ antibodies that circulate in the vasculature following systemic delivery. With robust efficacy in reversing AD-related pathology and an unexpected benefit in reducing CAA and associated micro-hemorrhages, icv-targeted passive immunotherapy offers a promising therapeutic approach for the long-term management of AD.Alzheimer disease ͉ passive immunotherapy ͉ vascular amyloid ͉ microglia ͉ peripheral sink

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