The utility of fluid biomarkers in research, trial design and clinical practice

Abstract

An optimistic and logical conclusion from recent clinical trials on AD disease-modifying drugs is that anti-Aβ compounds will be effective if therapy is initiated in a very early stage of the disease, before neurodegeneration is too severe. Therefore, we need sensitive and reliable tools to enable diagnosis of prodromal AD. Luckily, research advances have provided the field with both imaging (MRI and PET) and cerebrospinal fluid (CSF) biomarkers for this purpose. The CSF biomarkers total tau (reflecting neuronal degeneration), Aβ42 (reflecting Aβ deposition in plaques), and phosphorylated tau (probably related to tangle formation), have high diagnostic accuracy for AD dementia and can differentiate AD from normal aging and several important differential diagnoses. Large multi-center studies also show that that these CSF biomarkers can identify prodromal AD cases in MCI cohorts To enable a general introduction of CSF biomarkers in clinical routine, several standardization initiatives have been initiated by the Alzheimer's Association, including the Global Biomarker Standardization Consortium (GBSC) and the world-wide Quality Control (QC) program for CSF biomarkers. These efforts include establishing a reference method for CSF Aβ42 based on SRM Triple-Quad mass spectrometry. The interest in using biomarkers to study AD pathogenesis directly in man has increased. Some studies have evaluated CSF biomarkers in normal elderly to identify when in the preclinical phase of AD the biomarkers change from normal to positive and thereby which pathogenic process comes first in the disease course. Data so far largely come from single-LP cross-sectional studies with either clinical follow-up or extrapolation to symptoms onset, which leaves more than one option for interpretation of results. Last, CSF biomarkers may be valuable to monitor the biochemical effect of novel drugs directly in living AD patients. Results from early-phase BACE1 inhibitor trials indicate that CSF biomarkers (Aβ and sAPP isoforms) show the expected response to treatment. Such evidence of target engagement in man may be important to make the decision to proceed to large clinical trials. In addition, evidence from downstream biomarkers, such as T-tau and P-tau, may together with a favourable effect on cognition be essential for labelling a drug as disease-modifying.