{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:10:28Z","timestamp":1790017828196,"version":"4.0.1"},"reference-count":46,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T00:00:00Z","timestamp":1566172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["ARREST\u2010AD"],"award-info":[{"award-number":["ARREST\u2010AD"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Clinical trials targeting \u03b2\u2010amyloid peptides (A\u03b2) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or A\u03b2 being the wrong target. Targeting A\u03b2 to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of A\u03b2 for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal A\u03b2 deposition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA\u2010D). Mice were treated with a \u03b2\u2010site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3\u2010dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing A\u03b2 in cerebrospinal fluid (CSF) and brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF A\u03b2 increased with aging followed by a decrease of both A\u03b240 and A\u03b242 upon CAA onset, supporting the idea that combined reduction of CSF A\u03b240 and A\u03b242 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% A\u03b2 reduction in CSF and largely prevented CAA progression and associated pathologies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This is the first study showing that A\u03b2 reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for A\u03b2\u2010reducing treatments in patients at risk of CAA and in presymptomatic HCHWA\u2010D. 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