Antemortem CSF A42/A40 ratio predicts Alzheimer's disease pathology better than A42 in rapidly progressive dementias.

OBJECTIVE

Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF A42/A40 ratio. We compared CSF A42 and A42/A40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.

METHODS

We measured CSF A40 and A42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt-Jakob disease ( = 159), AD ( = 12), dementia with Lewy bodies (DLB,  = 4), AD/DLB mixed pathologies ( = 5), and various other pathologies ( = 31).

RESULTS

The score reflecting the severity of A pathology showed a better correlation with ln(A42/A40) (  = 0.506, = -0.713,  < 0.001) than with ln(A42) (  = 0.206, = -0.458,  < 0.001), which was confirmed after adjusting for covariates. A42/A40 ratio showed significantly higher accuracy than A42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with A42 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 A42/A40 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 A42/A40 ratio as a biomarker of AD pathophysiology and noninvasive screener for A pathology burden, and its introduction in the research diagnostic criteria for AD.