Early Aβ reduction prevents progression of cerebral amyloid angiopathy

Objective Clinical trials targeting beta-amyloid peptides (A beta) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or A beta being the wrong target. Targeting A beta to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of A beta 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 beta deposition. Methods APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing A beta in cerebrospinal fluid (CSF) and brain. Results 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 beta increased with aging followed by a decrease of both A beta 40 and A beta 42 upon CAA onset, supporting the idea that combined reduction of CSF A beta 40 and A beta 42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% A beta reduction in CSF and largely prevented CAA progression and associated pathologies. Interpretation This is the first study showing that A beta reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for A beta-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019