Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer's disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study

Abstract

Background: Despite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)₄₂ to detect amyloid pathology, the Aβ₄₂/Aβ₄₀ ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether Aβ₄₂ and amyR have different meanings and whether Aβ₄₀ represents more than an Aβ₄₂-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ₄₂ and amyR to detect AD pathology in terms of p-tau/Aβ₄₂ ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).

Methods: CSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ₄₂ and normal p-tau (A + T - = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A - T -). A + T - patients were further stratified into those with normal (CSFAβ₄₂ + /amyR - = 46) and pathological amyR (CSFAβ₄₂ + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ₄₂: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls.

Results: CSF Aβ₄₀ levels were the lowest in A - T - and in CSFAβ₄₂ + /amyR - , higher in CSFAβ₄₂ + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ₄₀ and p-tau in A - T - (β = 0.58; p < 0.001), CSFAβ₄₂ + /amyR - (β = 0.47; p < 0.001), and CSFAβ₄₂ + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ₄₀ (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ₄₀: + 4.5 z-score). CSFAβ₄₂ + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ₄₂ than CSFAβ₄₂ + /amyR - (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ₄₂ in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A - T - . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ₄₂ + /amyR - compared to controls, and further reduction in frontal areas in CSFAβ₄₂ + /amyR + , like in A + T + .

Conclusions: Pathological p-tau/Aβ₄₂ and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ₄₂ levels alone. AmyR positivity, associated with higher Aβ₄₀ levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.

Keywords: Alzheimer’s disease; Amyloid beta 40; Amyloid beta 42; Amyloid beta 42/40 ratio; Cerebrospinal fluid biomarkers; Fluorodeoxyglucose-positron emission tomography; Phosphorylated-tau.

Fig. 1

Intergroup differences of cerebrospinal fluid (CSF) biomarkers. The gray zone includes patients classified as A + T − . Dotted lines represent cut-off values used for Aβ₄₂, p-tau, and the p-tau/Aβ₄₂ cut-off 0.086; the dashed line represents p-tau/Aβ₄₂ cut-off 0.122. Bold lines represent comparisons with p-values < 0.05 at the Kruskal–Wallis

Fig. 2

Results of the robust locally weighted regression analysis showing changes of CSF biomarkers as a function of amyR. Values of p-tau, Aβ₄₂, and Aβ₄₀ are expressed as z-score standardized on the average and standard deviation of the A − T − group. The dotted line represents threshold value of pathological amyR (0.06), the dotted arrow indicates the point of change of Aβ₄₂ from normal to pathological values. CSF, cerebrospinal fluid; amyR, Aβ₄₂/Aβ₄₀; A, amyloid status; T, p-tau status)

Fig. 3

3D brain rendering showing significant clusters obtained in SPM when comparing A − T − vs. CSFAβ₄₂ + /amyR − (A) and CSFAβ₄₂ + /amyR − vs. CSFAβ₄₂ + /amyR + (B). Color scale represents t-statistics values