Plasma p-tau231 in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: A cross-sectional and longitudinal cohort study

Abstract

Introduction: Plasma phosphorylated tau (p-tau)-231 is a promising biomarker for Alzheimer's disease (AD), particularly in preclinical stages. We evaluated its diagnostic value in presenilin 1 (PSEN1) E280A mutation carriers versus non-carriers and compared it to p-tau217 and neurofilament light chain (NfL).

Methods: We analyzed plasma p-tau231 in 722 carriers and 640 non-carriers (ages 18-75). Longitudinal data from 164 carriers and 132 non-carriers were available, with 137 carriers and 109 non-carriers having p-tau231, p-tau217, and NfL levels. Analyses used linear mixed effects models and restricted cubic splines.

Results: E280A carriers had higher p-tau231 levels than non-carriers (9.0 ± 7.4 vs. 5.2 ± 3.4 pg/mL, P < 0.001). Baseline p-tau231 levels correlated with age, distinguishing carriers at age 23. Rates of change differed at age 19, ≈ 25 years before cognitive impairment. In a subset, p-tau231 changes differentiated carriers by age 20, earlier than p-tau217 and NfL.

Discussion: Plasma p-tau231 is a sensitive biomarker for early AD detection and progression monitoring.

Highlights: Plasma phosphorylated tau (p-tau)231 levels are associated with age in presenilin 1 carriers and non-carriers. Baseline p-tau231 levels diverged between carriers and non-carriers at age 23. Plasma p-tau231 changes distinguished carriers by age 19, at very early stages. P-tau231 longitudinal changes differentiate carriers earlier than p-tau217 or neurofilament light chain.

Keywords: Alzheimer's disease, autosomal dominant Alzheimer's disease; biomarkers, plasma, presenilin 1, phosphorylated tau231.

FIGURE 1

Baseline plasma p‐tau231 levels and rate of change in plasma p‐tau231 levels in mutation carriers and non‐carriers as a function of age. A, Cross‐sectional log‐transformed plasma p‐tau231 values of non‐carriers and mutation carriers as a function of age. B, Differences in log‐transformed plasma p‐tau231 values between carriers and non‐carriers. Non‐carrier levels are set at zero. The curves and credible intervals are drawn from the actual distributions of model fits derived by the Hamiltonian Markov chain Monte Carlo analyses. Baseline plasma p‐tau231 increases in PSEN1 E280A mutation carriers began to differ from non‐carriers at age 23, 21 years before the carriers’ estimated mean age of 44 at MCI onset. C, Longitudinal change rates of plasma p‐tau231 values as a function of age. D, Change rate differences between carriers and non‐carriers as a function of age. Non‐carrier rates are set at zero. The rate of p‐tau231 increases in PSEN1 E280A mutation carriers began to differ from non‐carriers at age 19, 25 years before the carriers’ estimated median age of 44 at MCI onset. Log‐transformed data were modeled using LMEMs, a restricted cubic spline, and Hamiltonian MCMC analyses. The shaded areas represent 99% credibility intervals. LMEM, linear mixed effects model; MCI, mild cognitive impairment; MCMC, Markov chain Monte Carlo; PSEN1, presenilin 1; p‐tau, phosphorylated tau.

FIGURE 2

Baseline plasma p‐tau231, p‐tau217, and NfL levels in mutation carriers and non‐carriers as a function of age. Top panel: cross‐sectional log‐transformed plasma p‐tau231, p‐tau217, and NfL values of non‐carriers and mutation carriers as a function of age. Bottom panel: differences in log‐transformed plasma p‐tau231, p‐tau217, and NfL values between carriers and non‐carriers. Non‐carrier levels are set at zero. The curves and credible intervals are drawn from the actual distributions of model fits derived by the Hamiltonian Markov chain Monte Carlo analyses. NfL, neurofilament light chain; PSEN1, presenilin 1; p‐tau, phosphorylated tau.

FIGURE 3

Rate of change in plasma p‐tau231, p‐tau217, and NfL levels in mutation carriers and non‐carriers as a function of age. Top panel: longitudinal change rates of plasma p‐tau231, p‐tau217, and NfL values as a function of age. Bottom panel: change rate differences between carriers and non‐carriers as a function of age. Non‐carrier rates are set at zero. The curves and credible intervals are drawn from the actual distributions of model fits derived by the Hamiltonian Markov chain Monte Carlo analyses. NfL, neurofilament light chain; PSEN1, presenilin 1; p‐tau, phosphorylated tau.