Differential roles of Alzheimer's disease plasma biomarkers in stepwise biomarker-guided diagnostics

Abstract

Introduction: This study aimed to investigate the differential roles of various plasma biomarkers in a stepwise diagnostic strategy for Alzheimer's disease (AD).

Methods: A total of 2984 participants, including 666 cognitively unimpaired (CU), 2032 with Alzheimer's clinical syndrome (ACS), and 286 non-ACS individuals, were recruited. Plasma amyloid beta (Aβ) 42/40, four phosphorylated tau (p-tau) epitopes, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels were measured using immunoassays.

Results: NfL demonstrated fair to excellent accuracy in differentiating non-ACS from CU groups (area under the curve [AUC], 0.79 to 0.94). p-tau217 had the highest accuracy for identifying Aβ (AUC 0.94) and tau positron emission tomography status (AUC 0.91). In the ACS group, p-tau217 was the strongest predictor of cognitive decline (p < .001).

Discussion: NfL may serve as a useful screening tool, while p-tau217 is particularly valuable for confirming AD pathology and prognosis.

Highlights: Plasma NfL could screen for cognitive impairment. p-tau217 reliably detects AD pathology, regardless of diagnosis. p-tau217 and GFAP predict prognosis in ACS. Each plasma biomarker plays a distinct role in stepwise AD diagnostics.

Keywords: Alzheimer's disease; neurofilament light chain; plasma biomarker; positron emission tomography; p‐tau217.

FIGURE 1

Performances of plasma biomarkers for (A) screening CI groups, (B) predicting Aβ(+) and tau(+) on PET, and (C) differentiating non‐ACS groups. (A) AUC values of plasma biomarkers for screening CI from CU groups. The dashed line indicates the AUC of the base model (age and sex), green indicates the AUC for plasma biomarker(s), and orange indicates the AUC for plasma biomarker(s) plus base model. (B) AUC values of plasma biomarkers for predicting Aβ(+) and tau(+) on PET. The dashed line indicates the AUC of the base model (age, sex, and APOE ε4 carrier status), green indicates the AUC for plasma biomarker(s), and orange indicates the AUC for plasma biomarker(s) plus base model. (C) AUC values of plasma biomarkers for differentiating Aβ(−) non‐ACS groups from Aβ(+) ACS. The error bar indicates 95% confidence interval. ACS, cognitive impairment with Alzheimer's clinical syndrome; AUC, area under the curve; Aβ, amyloid beta; CI, cognitive impairment; CU, cognitively unimpaired; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; PET, positron emission tomography; p‐tau, phosphorylated tau; SVCI, subcortical vascular cognitive impairment.

FIGURE 2

Partial correlation between plasma biomarker levels and both Aβ and tau uptakes. Bar indicates partial Spearman ρ of Aβ (green) and tau (orange) uptakes on plasma levels, after adjusting for age, sex, and counterpart pathology load. Specific contribution of Aβ and tau uptakes on each biomarker concentration was obtained as the percentage of partial Spearman ρ of each uptake over sum of partial Spearman ρ of Aβ and tau uptakes. CU, cognitively unimpaired; ACS, cognitive impairment with Alzheimer's clinical syndrome; SVCI, subcortical vascular cognitive impairment; Aβ, amyloid beta; p‐tau, phosphorylated tau; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain.

FIGURE 3

Prognostic performances of plasma biomarkers for predicting cognitive decline. The standardized regression coefficient (β) and p values are computed using linear regression with the annualized change in the CDR‐SB score as the dependent variable, adjusted for age, sex, years of education, and APOE ε4 carrier status. The black lines indicate the regression line for each group, and the error bands denote the 95% confidence intervals. The y‐axis represents the annualized change in CDR‐SB, and the x‐axis shows baseline plasma biomarker levels, measured in pg/mL for all biomarkers except Aβ42/40. ACS, cognitive impairment with Alzheimer's clinical syndrome; Aβ, amyloid beta; CDR‐SB, Clinical Dementia Rating‐Sum of Boxes; CU, cognitively unimpaired; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p‐tau, phosphorylated tau; SVCI, subcortical vascular cognitive impairment.

FIGURE 4

Distinctive role of plasma Alzheimer's disease biomarkers in stepwise biomarker‐guided diagnostics. ^* In cases where PET negative or positive subgroup included fewer than 10 participants, the selection of plasma biomarkers was based on the highest Cohen's d values. ^† Selected plasma biomarkers showed highest AUC for differentiating Aβ(−) SVCI or Aβ(−) FTD from Aβ(+) ACS. ^‡ For prognostic purposes, plasma biomarkers associated with a p value of less than .05 and the highest standardized regression coefficients were selected for each diagnostic group. ^§ Caution is needed due to limited statistical power from the small sample size. (SVCI, n = 130; FTD, n = 40). ACS, cognitive impairment with Alzheimer's clinical syndrome; Aβ, amyloid beta; p‐tau, phosphorylated tau; CU, cognitively unimpaired; FTD, frontotemporal dementia; GFAP, glial fibrillary acidic protein; NA, not available; NfL, neurofilament light chain; SVCI, subcortical vascular cognitive impairment.