The discovery and early validation of novel plasma biomarkers in mild-to-moderate Alzheimer's disease patients responding to treatment with rosiglitazone.

Author(s): Akuffo EL, Davis JB, Fox SM, Gloger IS, Hosford D, Kinsey EE, Jones NA, Nock CM, Roses AD, Saunders AM, Skehel JM, Smith MA, Cutler P

Affiliation(s): GlaxoSmithKline, New Frontiers Science Park, Harlow, UK.

Publication date & source: 2008-09, Biomarkers., 13(6):618-36.

Publication type: Clinical Trial, Phase II; Multicenter Study; Randomized Controlled Trial

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.