Use of theragnostic markers to select drugs for phase II/III trials for Alzheimer disease

Abstract

In a slowly progressive disorder like Alzheimer disease, evaluation of the clinical effect of novel drug candidates requires large numbers of patients and extended treatment periods. Current cell- and animal-based disease models of Alzheimer disease are poor at predicting a positive treatment response in patients. To help bridge the gap between disease models and large and costly clinical trials with high failure rates, biomarkers for the intended biochemical drug effect may be of value. Such biomarkers may be called 'theragnostic'. Here, we review the literature addressing the prospective value of these biomarkers.

Figure 1

Summary of candidate theragnostic biomarkers that reflect key drug targets in the Alzheimer disease (AD) process. Beta-secretase inhibitors should reduce cerebrospinal fluid (CSF) levels of amyloid beta (Aβ) isoforms starting at the first amino acid in the Aβ sequence (Aβ1-X). Gamma-secretase inhibitors should reduce Aβ1-40 and Aβ1-42 and increase Aβ1-14, Aβ1-15, and Aβ1-16. Both Aβ immunotherapy and anti-aggregation agents might be monitored by CSF levels of Aβ1-40 and Aβ1-42. Therapy-induced Aβ degradation might be monitored by CSF levels of different Aβ peptides, depending on the proteolytic pathway used for degradation. Aβ efflux from the brain to the blood might be monitored by measurement of Aβ in CSF and plasma. Inflammatory markers in plasma and CSF as well as CSF levels of CCL2 and chitotriosidase activity are putative markers of microglial activity and may change in response to treatments that influence microglial activity. Treatment with tau hyperphosphorylation inhibitors might be monitored with CSF phospho-tau (P-tau) levels. Downstream effects on axonal degeneration from disease-modifying treatments could be monitored by using the axonal damage markers CSF total tau (T-tau) and neurofilament light protein (NFL).