The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease

Abstract

Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals.

Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants.

Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals.

Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.

Keywords: Alzheimer's disease; magnetic resonance imaging; phosphorylated tau; plasma biomarkers.

FIGURE 1

Baseline comparisons of plasma biomarker concentrations across groups. (A) Plasma concentrations of P‐tau181, NfL, Aβ42, Aβ42/Aβ40, T‐tau, and GFAp are shown for CU, MCI, and AD (B) Plasma concentrations of P‐tau181, NfL, Aβ42, Aβ42/Aβ40, T‐tau, and GFAp are shown for MCI and MCI‐AD patients. Abbreviations: Aβ42/40, amyloid‐β42/40; AD, Alzheimer's disease; CU, cognitively unimpaired; GFAp; glial fibrillary acidic protein; MCI, mild cognitive impairment; NfL, neurofilament light; P‐tau181, phosphorylated tau 181; T‐tau, total tau. MCI = patients who did not progress to any type of dementia; MCI‐AD = patients who progressed to AD dementia. All P values are derived from a univariate linear model, adjusted for the effects of age, sex, APOE ε4 status, and education

FIGURE 2

Discriminative performance of biomarkers across diagnostic groups. Receiver‐operating characteristics (ROC) curves displaying the performance of plasma P‐tau181, NfL, Aβ42, Aβ42/Aβ40, T‐tau, and GFAp to distinguish (A) Alzheimer's disease (AD) dementia from cognitively unimpaired (CU), (B) mild cognitive impairment (MCI) from CU, (C) AD dementia from MCI, (D) individuals with MCI at baseline who later converted to AD dementia (MCI converters) from those who did not convert during the follow‐up, and (E) MCI converters versus CU. Abbreviations: Aβ42/40, amyloid‐β42/40; AD, Alzheimer's disease; AUC, area under the curve; CU, cognitively unimpaired; GFAp, glial fibrillary acidic protein; MCI, mild cognitive impairment; NfL, neurofilament light; P‐tau181, phosphorylated tau 181; T‐tau, total tau. MCI = patients who did not progress to any type of dementia; MCI‐AD = patients who progressed to AD dementia.

FIGURE 3

Baseline plasma biomarker concentrations and longitudinal cognitive decline. Plasma measures was used as continuous predictors, but for visualization purposes, the graphs show results for terciles (high, intermediate, and low concentration): (A) P‐tau181, (B) NfL, (C) Aβ42, (D) Aβ42/Aβ40, (E) T‐tau, and (F) GFAp at baseline. Abbreviations: Aβ42/40, amyloid‐β42/40; GFAp, glial fibrillary acidic protein; NfL, neurofilament light; P‐tau181, phosphorylated tau 181; T‐tau, total tau. Estimated means and 95% confidence interval (CI) from linear mixed‐effects models adjusted for age, sex, educational level, diagnosis, and APOE ε4 genotype.

FIGURE 4

Baseline and delta biomarker concentrations and longitudinal gray matter (GM) loss. T‐statistical parametric maps (P < 0.05, random field theory (RFT) corrected) showing the association between plasma measures at baseline and longitudinal gray matter loss (change GM volume; A). B shows the association between longitudinal plasma (change plasma) and change GM volume. Abbreviations: Aβ42/40, amyloid‐β42/40; GFAp, glial fibrillary acidic protein; NfL, neurofilament light; P‐tau181, phosphorylated tau 181; T‐tau, total tau