Plasma Alzheimer's disease biomarker relationships with incident abnormal amyloid PET

Abstract

Introduction: Limited data exist on the utility of plasma biomarkers to predict incident abnormal amyloid positron emission tomography (PET). In this study we evaluate the association of plasma Alzheimer's disease (AD) biomarkers with amyloid PET progression among initially amyloid PET negative (A-) individuals.

Methods: We included 290 A-, cognitively unimpaired Mayo Clinic Study of Aging participants. We estimated the association of each baseline plasma biomarker with progression from A- to A+ and with rate of amyloid PET change.

Results: Interquartile range differences in amyloid beta 42/40, percent phosphorylated tau 217 (%p-tau217), and Amyloid Probability Score 2 were associated with 1.29 (P = 0.09), 1.38 (P < 0.001), and 1.20 (P = 0.05) increases, respectively, in the hazard of progression from A- to A+ and 0.27 (P = 0.16), 0.50 (P = 0.007), and 0.28 (P = 0.15) Centiloid/year increases, respectively, in annual rate of amyloid PET change.

Discussion: Plasma %p-tau217 may be a useful screening tool to enrich for participants with increased likelihood of progressing from normal to abnormal amyloid PET in a primary prevention trial.

Highlights: Plasma phosphorylated tau 217 was associated with amyloid positron emission tomography progression, negative to positive. The associations were weaker for amyloid beta 42/40 and Amyloid Probability Score 2. Age and apolipoprotein E ε4 carriership were also important predictors. These markers may be useful for enrichment of a primary prevention trial.

Keywords: Alzheimer's disease; Alzheimer's disease biomarkers; Amyloid Probability Score 2; amyloid positron emission tomography; plasma amyloid beta 42/40; plasma phosphorylated tau 217.

FIGURE 1

Kaplan–Meier estimates for probability remaining A− by baseline plasma biomarker quartile. Participants were divided into four groups for each plasma biomarker using the 25th, 50th, and 75th percentiles as cut points. For Aβ42/40, the quartiles were defined as Q1, < 0.085; Q2, 0.085 to < 0.093; Q3 0.093 to < 0.104; and Q4, ≥ 0.104. For %p‐tau217, the quartiles were defined as Q1, < 0.37; Q2, 0.37 to < 0.68; Q3, 0.68 to < 0.97; Q4, ≥ 0.97. For the Amyloid Probability Score 2, the quartiles were defined as Q1, < 7; Q2, 7 to 10; Q3, 11 to 18; and Q4, ≥ 19. Note that lower values are more abnormal for Aβ42/40 while higher values are more abnormal for %p‐tau217 and Amyloid Probability Score 2. %p‐tau217, percent phosphorylated tau 217; Aβ, amyloid beta.

FIGURE 2

Line plots of individual amyloid PET Centiloid trajectories over time by baseline plasma biomarker quartile. Multiple colors were used to help differentiate trajectories of individual participants. Participants were divided into four groups for each plasma biomarker using the 25th, 50th, and 75th percentiles as cut points. For Aβ42/40, the quartiles were defined as Q1, < 0.085; Q2, 0.085 to < 0.093; Q3 0.093 to < 0.104; and Q4, ≥ 0.104. For %p‐tau217, the quartiles were defined as Q1, < 0.37; Q2, 0.37 to < 0.68; Q3, 0.68 to < 0.97; Q4, ≥ 0.97. For the Amyloid Probability Score 2, the quartiles were defined as Q1, < 7; Q2, 7 to 10; Q3, 11 to 18; and Q4, ≥ 19. The solid black lines with gray‐shaded regions represent the estimated mean (95% confidence interval) amyloid PET by time within each plasma biomarker quartile estimated from a linear regression model with generalized estimating equations. A separate model was fit for each plasma biomarker with amyloid PET Centiloid at each visit as the outcome and time, baseline plasma biomarker quartile, and the interaction of time and biomarker quartile as predictors. Figure S3 in supporting information shows the estimated mean curves for each biomarker on the same panel to facilitate comparison. %p‐tau217, percent phosphorylated tau 217; Aβ, amyloid beta; APS2, Amyloid Probability Score 2; PET, positron emission tomography.

FIGURE 3

Forest plots summarizing baseline plasma biomarker associations with progression from normal amyloid PET (A‒) to abnormal (A+) amyloid PET (left) and with annual rate of change in amyloid PET Centiloid (right). Hazard ratios (95% confidence intervals) were estimated from Cox proportional hazard models with time from A− to A+ as the outcome and baseline age, sex, APOE ε4 carriership, and baseline plasma biomarker level as predictors. Mean (95% confidence intervals) differences in annual rate of change in amyloid PET Centiloid were estimated from linear regression models with generalized estimating equations with amyloid PET Centiloid at each visit as the outcome and baseline age, sex, APOE ε4 carriership, baseline plasma biomarker level, time, and interactions with time and all other covariates as predictors. Separate models were fit for each plasma measure. Age associations are summarized for a 10 year difference. Plasma biomarker associations are summarized for an interquartile range difference: Aβ42/40, 0.019 lower; %p‐tau217, 0.60 higher; APS2, 12 higher. %p‐tau217, percent phosphorylated tau 217; Aβ, amyloid beta; APOE, apolipoprotein E; APS2, Amyloid Probability Score 2; CI, confidence interval; HR, hazard ratio; IQR, interquartile range; PET, positron emission tomography.