Cerebrospinal Fluid tau/β-Amyloid42 Ratio as a Prediction of Cognitive Decline in Nondemented Older Adults

Abstract

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 ␤-amyloid 40 (A␤ 40), A␤ 42 , tau, phosphorylated tau 181 , and plasma A␤ 40 and A␤ 42 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 A␤ 42 and increased levels of CSF tau and phosphorylated tau 181. Cerebrospinal fluid A␤ 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/A␤ 42 ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau 181 /A␤ 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 A␤ 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/A␤ 42 ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.

Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

“…In studies of nondemented older adults, higher CSF tau:A␤ 42 ratios were associated with higher rates of subsequent progression to the clinical stages of AD (34). The findings from these and other studies suggest that brain imaging and CSF measurements have complementary roles in the presymptomatic detection and tracking of AD.…”

Cerebrospinal fluid biomarkers of Alzheimer’s disease

“…Many studies demonstrated that the levels of CSF Aβ42 in AD are decreased compared with controls [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] . CSF Aβ42 can differentiate AD from controls with 89% sensitivity and 90% specificity [51] .…”

P1–206: Quantitative label‐free proteomics for discovery of biomarkers in cerebrospinal fluid: Assessment of technical and inter‐individual variation

“…All CDR 1 individuals had received a diagnosis of DAT. For each individual LP, fasted CSF (20-30 mL) was collected, gently mixed, centrifuged, aliquoted (0.5 mL) and frozen at 280uC in polypropylene tubes (2.0 mL tubes for storage) as described [3]. For preparation of pooled sample aliquots, all selected 0.5 mL samples were simultaneously thawed in an ice slurry within a 4uC room, combined and gently but thoroughly mixed in larger polypropylene tubes, re-aliquoted (0.5 mL) into fresh pre-chilled 2.0 mL polypropylene tubes, and frozen and stored at 280uC until use.…”

“…Pittsburgh compound B, or PIB) and positron emission tomography, or indirectly, by measuring low CSF beta-amyloid42 (Ab42) concentrations that correlate with amyloid deposition [3,[10][11][12][13][14]. Imaging and fluid biomarker studies have also shown potential to predict cognitive decline by measuring amyloid deposition [5], regional volumetric and metabolic changes in the brain [15][16][17], or specific changes in the CSF proteome (including concentrations of tau, YKL-40, VILIP-1, and calbindin, each in association with Ab42) [2,3,18,19]. CSF analysis may even allow classification of disease stage [20] and monitoring of acute changes in response to disease modifying therapies, as illustrated recently with gamma-secretase inhibitors [21].…”