Plasma amyloid, tau, and neurodegeneration biomarker profiles predict Alzheimer's disease pathology and clinical progression in older adults without dementia

Abstract

Introduction: Plasma markers have been reported to be associated with brain amyloid burden, tau pathology, or neurodegeneration. We aimed to evaluate whether plasma biomarker profiles could predict Alzheimer's disease (AD) pathology and clinical progression in older adults without dementia.

Methods: Cross-sectional and longitudinal data of participants enrolled in this study were from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Plasma amyloid beta (Aβ)_1-42/Aβ_1-40 ratio was selected as the marker for amyloid pathology, p-tau181 for tau pathology, and neurofilament light for neurodegeneration. Cut-offs for these plasma markers were calculated with well-established positron emission tomography and structural imaging biomarkers as reference. Older adults without dementia were categorized into eight groups at baseline by plasma amyloid/tau/neurodegeneration (A/T/N) cut-offs. Clinical progression was analyzed using linear mixed-effects models and Cox proportional hazard models.

Results: A total of 183 participants (97 cognitively normal [CN] subjects and 86 patients with mild cognitive impairment [MCI]; mean age 72.6 years, and 48.1% men) were included. Participants with A+ had significantly higher proportions of apolipoprotein E (APOE) gene ɛ4 carriers than those with A-. Brain atrophy was observed in all groups of CN, whereas cognition decline was obvious in the A+T+N+ group. Compared to A-T-N-, MCI patients with A+T+N+ had faster cognition worsening and faster brain atrophy. In the whole cohort, A+T+N+ and A+T+N- participants were at higher risk of clinical progression.

Discussion: Plasma A/T/N biomarker profiles may predict AD pathology and clinical progression, indicating a potential role for plasma biomarkers in clinical trials. More research is warranted to develop a robust plasma AD framework.

Keywords: Alzheimer's disease; amyloid beta; mild cognitive impairment; neurofilament light; plasma; p‐tau181.

FIGURE 1

ROC curves for plasma biomarker profiles based on PET or structural imaging. A, ROC curve generated from cut‐off analysis of plasma Aβ_1‐42/Aβ_1‐40 concentration ratios, based on amyloid PET abnormal versus normal. B, ROC curve generated from cut‐off analysis of plasma p‐tau181 concentration, based on tau PET abnormal versus normal. C, ROC curve generated from cut‐off analysis of plasma NfL level, based on adjusted hippocampus volume abnormal versus normal (by structural imaging MRI). Abbreviations: Aβ, amyloid beta; AUC, area under the ROC curve; NfL, neurofilament light; PET, positron emission tomography; ROC, receiver operating characteristic curve

FIGURE 2

Flowchart. Abbreviations: ADNI, Alzheimer's Disease Neuroimaging Initiative; CN, cognitively normal; MCI, mild cognitive impairment; NfL, neurofilament light

FIGURE 3

Change in clinical outcomes among four plasma A/T/N groups based on linear mixed‐effects regression models. A. Change in cognition among four plasma A/T/N groups. B. Change in brain volume among four plasma A/T/N groups. Analyses for clinical indicators were adjusted for age, sex, years of education, and APOE ε4 carriage. Change in clinical outcomes expressed as an annual percentage cognitive function scores and volume change, with 95% CI and P value. Abbreviations: A+, amyloid abnormal defined by plasma Aβ_1‐42/Aβ_1‐40 ratio; APOE, apolipoprotein E; CN, cognitively normal; MCI, mild cognitive impairment; N–, without neurodegeneration defined by plasma NfL; N+, with neurodegeneration defined by plasma NfL; T–, without tau pathology defined by plasma p‐tau181; T+, with tau pathology defined by plasma p‐tau181.

FIGURE 4

Kaplan‐Meier curves showing cumulative probability of disease progression. A. Kaplan‐Meier curves showing cumulative probability of progressing to CDR > or = 0.5 among cognitively normal participants. B. Kaplan‐Meier curves showing cumulative probability of progressive cognitive deterioration in patients with MCI. Abbreviations: A−, amyloid normal defined by plasma Aβ_1‐42/Aβ_1‐40 ratio; A+, amyloid abnormal defined by plasma Aβ_1‐42/Aβ_1‐40 ratio; MCI, mild cognitive impairment; N−, without neurodegeneration defined by plasma NfL; N+, with neurodegeneration defined by plasma NfL; T−, without tau pathology defined by plasma p‐tau181; T+, with tau pathology defined by plasma p‐tau181