Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of beta-amyloid (A beta) peptides in the walls of arteries both in the cortex and meninges. Here, we test the hypothesis that CAA results from the progressive accumulation of A beta in the perivascular interstitial fluid drainage pathways of the brain. Experimental studies have shown that interstitial fluid (ISF) from the rat brain flows along periarterial spaces to join the cerebrospinal fluid (CSF) to drain to cervical lymph nodes. Such lymphatic drainage plays a key role in B-cell and T-cell mediated immunity of the brain. Anatomical studies have defined periarterial ISF drainage pathways in the human brain that are homologous with the lymphatic pathways in the rat brain but are largely separate from the CSF. Periarterial channels in the brain in man are in continuity with those of leptomeningeal arteries and can be traced from the brain to the extracranial portions of the internal carotid arteries related to deep cervical lymph nodes. The pattern of deposition of A beta in senile plaques and in CAA suggests that A beta accumulates in pericapillary and periarterial ISF drainage pathways. A beta could accumulate in CAA due to either (i) increased production of A beta, (ii) reduced solubility of A beta peptides, or (iii) impedance of drainage of A beta along periarterial ISF drainage pathways within the brain and leptomeninges due to aging factors in cerebral arteries. Elucidation of factors that reduce elimination of A beta via perivascular drainage pathways may lead to their rectification and to new strategies for treatment of Alzheimer's disease.