Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma Aß42/Aß40 and p-tau.

INTRODUCTION: We studied usefulness of combining blood amyloid beta (Aß)42/Aß40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain Aß deposition in different stages of early Alzheimer's disease (AD). METHODS: Plasma biomarkers were measured using mass spectrometry (Aß42/Aß40) and immunoassays (p-tau217 and NfL) in cognitively unimpaired individuals (CU, N = 591) and patients with mild cognitive impairment (MCI, N = 304) from two independent cohorts (BioFINDER-1, BioFINDER-2). RESULTS: In CU, a combination of plasma Aß42/Aß40 and p-tau217 detected abnormal brain Aß status with area under the curve (AUC) of 0.83 to 0.86. In MCI, the models including p-tau217 alone or Aß42/Aß40 and p-tau217 had similar AUCs (0.86-0.88); however, the latter showed improved model fit. The models were implemented in an online application providing individualized risk assessments (https://brainapps.shinyapps.io/PredictABplasma/). DISCUSSION: A combination of plasma Aß42/Aß40 and p-tau217 discriminated Aß status with relatively high accuracy, whereas p-tau217 showed strongest associations with Aß pathology in MCI but not in CU.

Plasma Aß42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study.

BACKGROUND: To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer's disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aß) levels with the presence of pathological accumulation of Aß in the brain measured by amyloid-PET. Both plasma Aß42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. METHODS: We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aß40 and Aß42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aß-PET positive or negative, and the ability of TP42/40 to detect Aß-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aß biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. RESULTS: Eighteen (30.5%) subjects were Aß-PET positive. TP42/40 ratio alone identified Aß-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779-0.982). Discriminating performance of TP42/40 to detect Aß-PET-positive subjects yielded sensitivity and specificity values at Youden's cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aß-PET scans by 64%. Combination of both FDG-PET scores and plasma Aß biomarkers was found to be the most accurate Aß-PET predictor, with an AUC of 0.965 (95% CI = 0.913-0.100). CONCLUSIONS: Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aß positivity in preclinical and prodromal stages of Alzheimer's disease.