Hypothesized model of biomarker trajectories in AD based on cross-sectional data. (a) Amyloid (red) is identified by CSF Aβ42 or amyloid positron emission tomography (PET). Synaptic dysfunction (gold) is evidenced by fluorodeoxyglucose [F18] PET (FDG-PET), with dashed line indicating that abnormalities may be detected earlier than amyloid or functional magnetic resonance imaging (fMRI). Neuronal injury and/or neurofibrillary tangles are detected by CSF tau (and phosphorylated tau) (green), and brain structure/volume is evaluated by volumetric MRI (vMRI) (blue). Cognition is evaluated by clinical and psychometric testing (purple), whereas clinical function refers to cognitive and behavioral abilities that impact daily living (brown). Biomarkers change from normal to maximally abnormal (-axis) as a function of time (-axis), with typical clinical disease stages (preclinical, MCI, and dementia) separated by vertical dashed lines. (b) The long preclinical stage is further characterized by hypothesized progressive stages. Stage 1 is defined as asymptomatic cerebral amyloidosis (abnormal CSF Aβ42 and/or amyloid PET). Stage 2 is defined as asymptomatic cerebral amyloidosis with concomitant evidence of neuronal injury/degeneration (abnormal CSF tau/ptau and/or vMRI). Stage 3 is defined as asymptomatic cerebral amyloidosis with evidence of neuronal injury/degeneration and subtle cognitive/behavioral decline (as defined by clinical and/or psychometric testing). Adapted with permission from Jack et al. [90].