Table 1 Role of biomarkers in AD drug development

Identification of trial population

Presence of presenilin 1 (PS1), presenilin 2 (PS2), or amyloid precursor protein (APP) mutations; ApoE-4 plus TOMM40; trisomy 21

Confirmation of diagnosis; exclude non-AD diagnoses

Amyloid imaging; CSF AD signature

Prognosis and course projection

In MCI, ApoE-4 carriers progress more rapidly

Amyloid production and clearance (target engagement)

Stable isotope-labeled kinetics (SILK); BACE activity reduction with BACE inhibitor; CSF Aβ reduction by BACE inhibitor or gamma-secretase inhibitor

Impact of therapy on brain circuit and network function

fMRI; EEG

Impact of therapy on intermediate targets

Amyloid imaging; CSF amyloid; tau PET; CSF phospho-tau

Disease modification

MRI atrophy; CSF total tau; FDG PET; neurofilament light

Stratification for trial analysis

ApoE-4 genotype

Side effect monitoring

MRI surveillance for amyloid-related imaging abnormalities (ARIA); liver function tests; complete blood counts; electrocardiography