Cerebrospinal fluid amyloid-β 42/40 ratio in clinical setting of memory centers: a multicentric study

Introduction: The cerebrospinal fluid (CSF) biomarkers amyloid-beta(A beta), tau and phosphorylated tau (p-tau181) are now used for the diagnosis of Alzheimer's disease (AD). A beta 40 is the most abundant A beta peptide isoform in the CSF, and the A beta 42/40 ratio has been proposed to better reflect brain amyloid production. However, its additional value in the clinical setting remains uncertain. Methods: A total of 367 subjects with cognitive disorders who underwent a lumbar puncture were prospectively included at three French memory centers (Paris-North, Lille and Montpellier; the PLM Study). The frequency of positive, negative and indeterminate CSF profiles were assessed by various methods, and their adequacies with the diagnosis of clinicians were tested using net reclassification improvement (NRI) analyses. Results: On the basis of local optimum cutoffs for A beta 42 and p-tau181, 22% of the explored patients had indeterminate CSF profiles. The systematic use of A beta 42/40 ratio instead of A beta 42 levels alone decreased the number of indeterminate profiles (17%; P = 0.03), but it failed to improve the classification of subjects (NRI = -2.1%; P = 0.64). In contrast, the use of A beta 42/40 ratio instead of A beta 42 levels alone in patients with a discrepancy between p-tau181 and A beta 42 led to a reduction by half of the number of indeterminate profiles (10%; P < 0.001) and was further in agreement with clinician diagnosis (NRI = 10.5%; P = 0.003). Conclusions: In patients with a discrepancy between CSF p-tau181 and CSF A beta 42, the assessment of A beta 42/40 ratio led to a reliable biological conclusion in over 50% of cases that agreed with a clinician's diagnosis.