Unravelling the Association Between Amyloid-PET and Cerebrospinal Fluid Biomarkers in the Alzheimer’s Disease Spectrum: Who Really Deserves an A+?

Abstract

Background:

Association between cerebrospinal fluid (CSF)-amyloid-β (Aβ)₄₂ and amyloid-PET measures is inconstant across the Alzheimer’s disease (AD) spectrum. However, they are considered interchangeable, along with Aβ_42/40 ratio, for defining ‘Alzheimer’s Disease pathologic change’ (A+).

Objective:

Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients.

Methods:

We included 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aβ₄₂ within a 365-days interval. Thresholds used for dichotomization were: Aβ₄₂ < 640 pg/mL (Aβ₄₂+); pTau > 61 pg/mL (pTau+); and Aβ_42/40 < 0.069 (AD_ratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPM_CL, SPM_AAL, FS_GM, FS_WC).

Results:

Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho = 0.93–0.99). The most significant findings were: pTau positive correlation with SPM_CL SUVR (rho = 0.56, p = 0.0063) and Aβ_42/40 negative correlation with SPM_CL and SPM_AAL SUVRs (rho = –0.56, p = 0.0058; rho = –0.52, p = 0.0117 respectively). No correlations between CSF-Aβ₄₂ and global SUVRs were observed. In subregion analysis, both pTau and Aβ_42/40 values significantly correlated with cingulate SUVRs from any pipeline (R² = 0.55–0.59, p < 0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aβ_42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aβ₄₂ or using Aβ_42/40, instead of Aβ₄₂ alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids.

Conclusion:

We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aβ_42/40 and secondarily pTau rather than Aβ₄₂ levels.