Antemortem CSF A β 42/A β 40 ratio predicts Alzheimer's disease pathology better than A β 42 in rapidly progressive dementias

Objective Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A β 42 values in vivo with postmortem Alzheimer's disease ( AD ) pathology, while none evaluated the CSF A β 42/A β 40 ratio. We compared CSF A β 42 and A β 42/A β 40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death. Methods We measured CSF A β 40 and A β 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 β pathology showed a better correlation with ln(A β 42/A β 40) ( R 2  = 0.506, β  = −0.713, P  < 0.001) than with ln(A β 42) ( R 2  = 0.206, β  = −0.458, P  < 0.001), which was confirmed after adjusting for covariates. A β 42/A β 40 ratio showed significantly higher accuracy than A β 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 β 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 β 42/A β 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 β 42/A β 40 ratio as a biomarker of AD pathophysiology and noninvasive screener for A β pathology burden, and its introduction in the research diagnostic criteria for AD .