The role of biomarkers in clinical trials for Alzheimer disease

Abstract

Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer's Association's Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.

FIGURE 1

Study design summaries for disease modification.

FIGURE 2

Correlation between PIB-derivative binding and β-amyloid levels in brain slices.

FIGURE 3

Potential biochemical biomarkers in AD. Question marks indicate processes or anatomic areas that may be proximal in the disease process. Possible biomarkers that can be considered given these postulated disease processes include tau, phospho-tau, sulfatides, cholesterol, isoprostanes, and Aβ42.

FIGURE 4

Products of reactive oxygen species–dependent attack of different substrates (nucleic acid, protein, lipid) and relative most employed analytical methods (GC/MS: gas chromatography/mass spectrometry; HPLC: high performance liquid chromatography; ELISA: enzyme-linked immuno-assay; 8-OH-G: 8-hydroxyguanosine; MDA: malondialdehyde; LOOH: lipid hydroperoxide; HNE: 4-hydroxynonenal).

FIGURE 5

The four classes of F₂-isoprostane deriving from the ROS-mediated oxidation of arachidonic acid.

FIGURE 6

Inflammatory changes implicated in Alzheimer disease (AD). This conceptual scheme of the cytokine cycle illustrates the relationship of glial activation and inflammatory cytokine overexpression to neurodegenerative events in AD, with the effect of overexpression of IL-1 in the brain. IL-1 = interleukin-1; APOE = Apolipoprotein E; ACT = antichymotrypsin; sAPP = secreted amyloid precursor; iNOS = nitric oxide synthase; Cac = activated complement; MCI = mild cognitive impairment.