To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals.Design
Evaluation of CSF β-amyloid40 (Aβ40), Aβ42, tau, phosphorylated tau181, and plasma Aβ40 and Aβ42 and longitudinal clinical follow-up (from 1 to 8 years).Setting
Longitudinal studies of healthy aging and dementia through an AD research center.Participants
Community-dwelling volunteers (n = 139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia.Results
Individuals with very mild or mild AD have reduced mean levels of CSF Aβ42 and increased levels of CSF tau and phosphorylated tau181. Cerebrospinal fluid Aβ42 level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Aβ42 ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58–17.22) and phosphorylated tau181/Aβ42 ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62–11.86) predict conversion from a CDR of 0 to a CDR greater than 0.Conclusions
The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Aβ42, when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Aβ42 ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.