Table 2.

Use of fluid biomarkers in Alzheimer disease clinical trials

Application	Rationale	Time point for use	Comment
Enrichment of AD cases	CSF biomarkers may be valuable in clinical trials on early AD or MCI, to improve the diagnostic accuracy and enrich the patient sample with genuine AD cases	Baseline evaluation of CSF biomarkers in cases eligible for the trial	High T-tau and P-tau and low Aβ42 are indicative of AD
Post-hoc patient stratification	AD cases with biomarker evidence of a clear disturbance in the Aβ metabolism may have a more clear-cut effect of anti-Aβ disease-modifying drugs	Post-hoc stratification of AD cases based on baseline CSF biomarker data	CSF Aβ42 may be valuable to stratify AD cases enrolled in a trial on an anti-Aβ disease-modifying drug candidate CSF P-tau may be valuable to stratify AD cases enrolled in a trial on a drug targeting tau phosphorylation and tangle pathology
Safety monitoring	CSF biomarkers may, together with MRI scans, be used to identify cases with meningoencephalitis or vasogenic edema in Aβ immunotherapy clinical trials	Baseline evaluation CSF biomarkers to allow comparison with a CSF sample taken in the case of an adverse event	CSF cell count, IgG/IgM index, and IgG/IgM oligoclonal bands are standard measures to identify and monitor an inflammatory process, such as meningoencephalitis, within the CNS CSF/serum albumin ratio is the standard measure to identify and monitor a disturbance in the blood–brain barrier causing cerebral edema
Monitoring of drug activity on pathogenic processes	CSF biomarkers may provide information that the drug has an effect on a specific pathogenic process directly in patients with AD	Evaluation of CSF biomarkers in samples taken at baseline compared with samples taken at time points during the trial, including the last week of the trial	Primary CSF biomarkers for APP/Aβ metabolism (e.g., Aβ42, sAPPβ, BACE1 activity, and Aβ turnover) may give biochemical evidence for the specific effect of an anti-Aβ drug candidate. Downstream CSF biomarkers (e.g., P-tau and T-tau) may give biochemical evidence for downstream effects on tangle pathology and axonal degeneration of an anti-Aβ drug candidate

Abbreviations: AD, Alzheimer disease; APP, amyloid precursor protein; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; T-tau, total tau; P-tau, phosphorylated tau.