Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes

Abstract

<p><strong>Introduction: </strong>Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (A<em>β</em>) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented.<br></p><p><strong>Methods: </strong>Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 <em>μ</em>g (<em>n</em> = 42) or placebo (<em>n</em> = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up A<em>β</em> positron emission tomography (PET) scans at 18 to 24 months.<br></p><p><strong>Results: </strong>CAD106 induced measurable serum A<em>β</em> immunoglobulin G titers in 41/42 participants, slower rates of A<em>β</em> plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; <em>P</em> < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic).<br></p><p><strong>Discussion: </strong>Despite early termination, these findings support the potential value of conducting larger prevention trials of A<em>β</em> active immunotherapies in individuals at risk for AD.<br></p><p><strong>Highlights: </strong>This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.</p>