Risk factors associated with beta-amyloid(1-42) immunotherapy in preimmunization gene expression patterns of blood cells.
BACKGROUND
A phase 2a, double-blind, placebo-controlled, multicenter study was conducted to evaluate safety, tolerability, and pilot efficacy of immunization with beta-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.


METHODS
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.
O'Toole
Margot
M
Biological Technologies, Wyeth Research, Cambridge, MA 02140, USA. mtoole@wyeth.com
Janszen
Derek B
DB
Slonim
Donna K
DK
Reddy
Padmalatha S
PS
Ellis
Debra K
DK
Legault
Holly M
HM
Hill
Andrew A
AA
Whitley
Maryann Z
MZ
Mounts
William M
WM
Zuberek
Krystyna
K
Immermann
Frederick W
FW
Black
Ronald S
RS
Dorner
Andrew J
AJ
D000544:Alzheimer Disease / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis*; D004660:Encephalitis / Q000209:etiology* / Q000235:genetics; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D012307:Risk Factors
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D012333:RNA, Messenger