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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 .

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