Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults.
OBJECTIVE
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.


METHODS
Evaluation of CSF beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(42) and longitudinal clinical follow-up (from 1 to 8 years).


METHODS
Longitudinal studies of healthy aging and dementia through an AD research center.


METHODS
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 Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(42) level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(42) 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 Abeta(42), 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/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.
Fagan
Anne M
AM
Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, Box 8111, St Louis, MO 63110, USA. fagana@neuro.wustl.edu
Roe
Catherine M
CM
Xiong
Chengjie
C
Mintun
Mark A
MA
Morris
John C
JC
Holtzman
David M
DM
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid*; D016009:Chi-Square Distribution; D003072:Cognition Disorders / Q000097:blood / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D003704:Dementia / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid*; D011237:Predictive Value of Tests; D016875:tau Proteins / Q000097:blood / Q000134:cerebrospinal fluid*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins