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Risk Factors Associated With  -Amyloid(1-42) Immunotherapy in Preimmunization Gene Expression Patterns of Blood Cells
Margot O’Toole, PhD;
Derek B. Janszen, PhD;
Donna K. Slonim, PhD;
Padmalatha S. Reddy, PhD;
Debra K. Ellis, BS;
Holly M. Legault, BS;
Andrew A. Hill, PhD;
Maryann Z. Whitley, PhD;
William M. Mounts, MS;
Krystyna Zuberek, BS;
Frederick W. Immermann, PhD;
Ronald S. Black, MD;
Andrew J. Dorner, PhD
Arch Neurol. 2005;62:1531-1536.
Background A phase 2a, double-blind, placebo-controlled, multicenter study was conducted to evaluate safety, tolerability, and pilot efficacy of immunization with  -amyloid(1-42) in patients with Alzheimer disease. Six immunizations were planned but were halted when meningoencephalitis was recognized as an adverse event in 6% of immunized patients.
Objective To identify biomarkers associated with both the risk of meningoencephalitis and antibody responsiveness.
Participants One hundred fifty-three patients with mild to moderate Alzheimer disease.
Main Outcome Measure Association between response to immunization and preimmunization expression levels of 8239 messenger RNA transcripts expressed in peripheral blood mononuclear cells that had been collected at the screening visit.
Results Expression patterns of genes related to apoptosis and proinflammatory pathways (tumor necrosis factor pathway in particular) were identified as biomarkers of risk for the development of meningoencephalitis. Expression patterns of genes related to protein synthesis, protein trafficking, DNA recombination, DNA repair, and cell cycle were strongly associated with IgG response to immunization.
Conclusions Candidate biomarkers associated with risk of immunotherapy-related meningoencephalitis were detected in blood collected prior to treatment. In addition, a different set of biomarkers were identified that were associated with the desired outcome of IgG response.
Author Affiliations: Biological Technologies (Drs O’Toole, Slonim, Reddy, Hill, Whitley, and Dorner; Mss Ellis, Legault, and Zuberek, and Mr Mounts), Wyeth Research, Cambridge, Mass; Preclinical Biostatistics (Drs Janszen and Immermann), Wyeth Research, Collegeville, Pa; and Clinical Research (Dr Black), Wyeth Research, Pearl River, NY. Dr Slonim is now with the Department of Computer Science, Tufts University, Medford, Mass, and Ms Zuberek is now with Cell Signal Technology, Beverly, Mass.
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