Cerebrospinal fluid tau/β-amyloid₄₂ ratio as a prediction of cognitive decline in nondemented older adults

Objectives: 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-amyloid ₄₀ (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.