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Anne M. Fagan, PhD; Catherine M. Roe, PhD; Chengjie Xiong, PhD; Mark A. Mintun, MD; John C. Morris, MD; David M. Holtzman, MD

Arch Neurol. 2007;64(3):343-349. Published online January 8, 2007 (doi:10.1001/archneur.64.3.noc60123).

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-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.

Author Affiliations: Departments of Neurology (Drs Fagan, Morris, and Holtzman), Biostatistics (Drs Roe and Xiong), Radiology (Dr Mintun), Pathology and Immunology (Dr Morris), and Molecular Biology and Pharmacology (Dr Holtzman), Hope Center for Neurological Disorders (Drs Fagan and Holtzman), and Alzheimer's Disease Research Center (Drs Fagan, Roe, Xiong, Mintun, Morris, and Holtzman), Washington University School of Medicine, St Louis, Mo.

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