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

Abstract

Objective: Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF Aβ42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF Aβ42/Aβ40 ratio. We compared CSF Aβ42 and Aβ42/Aβ40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.

Methods: We measured CSF Aβ40 and Aβ42 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 Aβ pathology showed a better correlation with ln(Aβ42/Aβ40) (R ² = 0.506, β = -0.713, P < 0.001) than with ln(Aβ42) (R ² = 0.206, β = -0.458, P < 0.001), which was confirmed after adjusting for covariates. Aβ42/Aβ40 ratio showed significantly higher accuracy than Aβ42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with Aβ42 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 Aβ42/Aβ40 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 Aβ42/Aβ40 ratio as a biomarker of AD pathophysiology and noninvasive screener for Aβ pathology burden, and its introduction in the research diagnostic criteria for AD.

Figure 1

Comparison of Aβ neuropathological score, CSF Aβ42 levels (pg/mL), and CSF Aβ42/Aβ40 ratio across the Thal's phases of Aβ pathology.31 Data are expressed as median and interquartile range (IQR).

Figure 2

Correlations between CSF ln(Aβ42) levels, ln(Aβ42/Aβ40) values, and Aβ‐related pathology. (A) A significant negative correlation is seen between CSF ln(Aβ42) levels and Aβ pathology score (R ² = 0.206, β = −0.458, P < 0.001). (B) In comparison to (A) the negative correlation between CSF ln(Aβ42/Aβ40) and Aβ pathology score is significantly higher (R ² = 0.506, β = −0.713, P < 0.001).

Figure 3

Distribution of AD pathological changes at each given range of CSF Aβ42/Aβ40 ratio values. Aβ, amyloid beta; NF, neurofibrillary pathology; n, number of cases.