The discovery and early validation of novel plasma biomarkers in mild-to-moderate Alzheimer's disease patients responding to treatment with rosiglitazone.
Recent advances in clinical, pathological and neuroscience studies have identified disease-modifying therapeutic approaches for Alzheimer's disease that are now in clinical trials. This has highlighted the need for reliable and convenient biomarkers for both early disease diagnosis and a rapid signal of drug efficacy. We describe the identification and assessment of a number of candidate biomarkers in patients with Alzheimer's disease and the correlation of those biomarkers with rosiglitazone therapeutic efficacy, as represented by a change in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Plasma from 41 patients with Alzheimer's disease were analysed by open platform proteomics at baseline and after receiving 8 mg rosiglitazone for 24 weeks. From a comparison of protein expression following treatment with rosiglitazone, 97 proteins were observed to be differentially expressed with a p-value<0.01. From this analysis and comparison to recently published data from our laboratory, a prioritized list of 10 proteins were analysed by immunoassay and/or functional assay in a wider set of samples from the same clinical study, representing a rosiglitazone dose response, in order to verify the changes observed. A number of these proteins appeared to show a correlation with change in ADAS-Cog at the higher treatment doses compared with the placebo. Alpha-2-macroglobulin, complement C1 inhibitor, complement factor H and apolipoprotein E expression showed a correlation with ADAS-Cog score at the higher doses (4 mg and 8 mg). These results are discussed in light of the pathology and other recently published data.
Akuffo
Emma L
EL
GlaxoSmithKline, New Frontiers Science Park, Harlow, UK.
Davis
John B
JB
Fox
Steven M
SM
Gloger
Israel S
IS
Hosford
David
D
Kinsey
Emma E
EE
Jones
Neil A
NA
Nock
Christina M
CM
Roses
Allen D
AD
Saunders
Ann M
AM
Skehel
J Mark
JM
Smith
Marjorie A
MA
Cutler
Paul
P
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D001057:Apolipoproteins E / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D003071:Cognition / Q000187:drug effects*; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D050718:Complement C1 Inhibitor Protein; D017242:Complement Factor H / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D018697:Nootropic Agents / Q000627:therapeutic use*; D040901:Proteomics; D015203:Reproducibility of Results; D000077154:Rosiglitazone; D012720:Severity of Illness Index; D045162:Thiazolidinediones / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D000511:alpha-Macroglobulins / Q000378:metabolism
D001057:Apolipoproteins E; D015415:Biomarkers; C493495:CFH protein, human; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D018697:Nootropic Agents; C469952:SERPING1 protein, human; D045162:Thiazolidinediones; D000511:alpha-Macroglobulins; D000077154:Rosiglitazone; D017242:Complement Factor H