Antemortem CSF Aβ42/Aβ40 ratio predicts Alzheimer's disease pathology better than Aβ42 in rapidly progressive dementias

Objective Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A beta 42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF A beta 42/A beta 40 ratio. We compared CSF A beta 42 and A beta 42/A beta 40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death. Methods We measured CSF A beta 40 and A beta 42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt-Jakob disease (n = 159), AD (n = 12), dementia with Lewy bodies (DLB, n = 4), AD/DLB mixed pathologies (n = 5), and various other pathologies (n = 31). Results The score reflecting the severity of A beta pathology showed a better correlation with ln(A beta 42/A beta 40) (R-2 = 0.506, beta = -0.713, P < 0.001) than with ln(A beta 42) (R-2 = 0.206, beta = -0.458, P < 0.001), which was confirmed after adjusting for covariates. A beta 42/A beta 40 ratio showed significantly higher accuracy than A beta 42 in the distinction between cases with or without AD pathology (AUC 0.818 +/- 0.028 vs. 0.643 +/- 0.039), especially in patients with A beta 42 levels <= 495 pg/mL (AUC 0.888 +/- 0.032 vs. 0.518 +/- 0.064). Using a cut-off value of 0.810, the analysis of A beta 42/A beta 40 ratio yielded 87.0% sensitivity, 88.2% specificity in the distinction between cases with an intermediate-high level of AD pathology and those with low level or no AD pathology. Interpretation The present data support the use of CSF A beta 42/A beta 40 ratio as a biomarker of AD pathophysiology and noninvasive screener for A beta pathology burden, and its introduction in the research diagnostic criteria for AD.