Plasma p-tau217, p-tau181, and NfL as early indicators of dementia risk in a community cohort: The Shanghai Aging Study

Abstract

Introduction: Blood biomarkers showed values for predicting future cognitive impairment. Evidence from the community-based cohort was limited only in high-income countries.

Methods: This study included 1857 dementia-free community residents recruited in 2009-2011 and followed up in waves 2014-2016 and 2019-2023 in the Shanghai Aging Study. We intended to explore the relationships of baseline plasma ALZpath phosphorylated tau 217 (p-tau217), p-tau181, neurofilament light chain (NfL) with follow-up incident dementia, Alzheimer's disease (AD), and amyloidosis.

Results: Higher concentrations of plasma p-tau217, p-tau181, and NfL were correlated to higher decline speed of Mini-Mental State Examination score, and higher risk of incident dementia and AD. The p-tau217 demonstrated a significant correlation with longitudinal neocortical amyloid-beta (Aβ) deposition (r = 0.57 [0.30, 0.76]) and a high accuracy differentiating Aβ+ from Aβ- at follow-ups (area under the receiver operating characteristic curve = 0.821 [0.703, 0.940]).

Discussion: Plasma p-tau217 may be an early predictive marker of AD and Aβ pathology in older community-dwelling individuals.Highlights: Plasma p-tau217, p-tau181, and NfL were positively associated with long-term cognitive decline and risk of incident dementia.Plasma p-tau217 showed a better performance distinguishing Aβ+ individuals from Aβ- individuals at follow-ups.Plasma NfL may be a suitable predictor of general cognitive decline in older community-dwelling individuals.

Keywords: Alzheimer's disease; Aβ; biomarker; cohort; community; dementia.

FIGURE 1

Plasma p‐tau217, p‐tau181, and NfL in different diagnostic groups at baseline, and the correlations with baseline MMSE. In (A–C), ANCOVA and post hoc tests based on estimated marginal means (Bonferroni method for adjusting multiple comparisons) were used to test the difference of plasma biomarkers among baseline diagnostic groups after adjusting for age, sex, years of education, and APOE ε4. *p < 0.05, **p < 0.01, and ***p < 0.001. In (D–F), the β with the 95% confidence interval from the univariate linear regression model indicated the association between baseline biomarkers and baseline MMSE. aMCI‐MD, amnestic mild cognitive impairment‐multiple domains; aMCI‐SD, amnestic mild cognitive impairment‐single domain; ANCOVA, analysis of covariance; APOE, apolipoprotein E; CI, confidence interval; CU, cognitively unimpaired; MMSE, Mini‐Mental State Examination; naMCI‐MD, non‐amnestic mild cognitive impairment‐multiple domains; naMCI‐SD, non‐amnestic mild cognitive impairment‐single domain; NfL, neurofilament light chain.

FIGURE 2

Correlations of baseline plasma biomarkers and longitudinal MMSE trajectory. In (A–C), multivariate linear regression model with β was used to assess the association between baseline plasma biomarkers and MMSE declining rate adjusting for age, sex, years of education, and APOE ε4. In (D–F), linear mixed‐effects model was used to fit the association between follow‐up time×quartered biomarker levels and MMSE with individualized random intercept and fixed slope, adjusting for age, sex, year of education, and APOE ε4. The slopes of MMSE decline among four levels were compared. *p < 0.05, **p < 0.01, and ***p < 0.001. The p‐tau217 Q1, < 0.24 pg/mL; Q2, ≥ 0.24 and < 0.31 pg/mL; Q3, ≥ 0.31 and < 0.43 pg/mL; Q4, ≥ 0.43 pg/mL. The p‐tau181 Q1, < 1.47 pg/mL; Q2, ≥ 1.47, and < 1.90 pg/mL; Q3, ≥ 1.90 and < 2.49 pg/mL; Q4, ≥ 2.49 pg/mL. NfL Q1, < 11.75 pg/mL; Q2, ≥ 11.75 and < 15.49 pg/mL; Q3, ≥ 15.49 and < 20.89 pg/mL; Q4, ≥ 20.89 pg/mL. APOE, apolipoprotein E; CI, confidence interval; MMSE, Mini‐Mental State Examination; NfL, neurofilament light chain.

FIGURE 3

Associations of plasma p‐tau217, p‐tau181, NfL, and incident dementia/AD. In the multivariate Cox regression model, age, sex, education year, and APOE ε4 were adjusted. The linear trend was tested by entering the median value of each quartile of biomarker concentration as a continuous variable in the Cox regression model. *p < 0.05, **p < 0.01, and ***p < 0.001. The p‐tau217 Q1, < 0.24 pg/mL; Q2, ≥ 0.24 and < 0.31 pg/mL; Q3, ≥ 0.31 and < 0.43 pg/mL; Q4, ≥ 0.43 pg/mL. The p‐tau181 Q1, < 1.47 pg/mL; Q2, ≥ 1.47, and < 1.90 pg/mL; Q3, ≥ 1.90 and < 2.49 pg/mL; Q4, ≥ 2.49 pg/mL. NfL Q1, < 11.75 pg/mL; Q2, ≥ 11.75 and < 15.49 pg/mL; Q3, ≥ 15.49 and < 20.89 pg/mL; Q4, ≥ 20.89 pg/mL. AD, Alzheimer's disease; CI, confidence interval; HR, hazard ratio; NfL, neurofilament light chain.

FIGURE 4

Plasma p‐tau217, p‐tau181, NfL, and follow‐up Aβ‐PET. (A)–(C) showed the concentrations of 10‐year‐ago baseline plasma biomarkers in Aβ negative vs. Aβ positive. (D)‐(F) demonstrated the association between baseline plasma biomarkers and neocortical Aβ SUVR. Pearson's correlation (r) with 95% CI was indicated accordingly. (G) Presented the predictive value of baseline biomarkers for follow‐up Aβ positive. (H) Illustrated the voxel‐wise association of baseline plasma biomarkers with Aβ PET. Colored regions were statistically significant with uncorrected p < 0.001 with a cluster size of k > 100 voxels. *p < 0.05, **p < 0.01, and ***p < 0.001. Aβ, amyloid‐beta; AUC, area under the curve; CI, confidence interval; NfL, neurofilament light chain; PET, positron emission tomography; PPV, positive predictive value; NPV, negative predictive value; SUVR, standardized uptake value ratio.