Real world diagnostic performance of plasma p-tau217 for early-onset Alzheimer's disease in a cognitive disorders tertiary care setting

Abstract

BackgroundPlasma p-tau217 shows exceptional diagnostic performance for Alzheimer's disease (AD) in cohort studies. Recent real-world studies support its validity in more diverse populations.ObjectiveTest the performance of plasma p-tau217 in representative real-world early-onset cognitive disorders patients.Methods118 adult patients with cognitive complaints or potential neurodegenerative diseases (ND) from a single healthcare network in Melbourne, Australia, were categorized into three groups based on clinical diagnosis: non-ND (n = 52), early-onset AD (EOAD, n = 39), and non-AD ND (other-ND, n = 27). Plasma p-tau217 was measured using the Simoa^® ALZpath p-Tau 217 Assay.ResultsPlasma p-tau217 was elevated in EOAD (mean ± SD: 1.13 ± 0.51) compared with non-ND (0.31 ± 0.27, p = 5.43e-23) and other-ND (0.23 ± 0.10, p = 9.65e-21). ROC analysis revealed excellent diagnostic performance, with AUCs of 0.944 [95% CI:0.893-0.996] for EOAD versus non-ND and 0.984 [0.962-1.000] for EOAD versus other-ND. Using a binary cut-off (p-tau217 > 0.42 pg/mL), 17% non-ND, 95% EOAD and 7% other-ND were A + . Using a two-tiered cut-off approach (0.40 pg/mL > p-tau217 > 0.63 pg/mL), 4% non-ND, 94% EOAD and 0% other-ND were A + . 10% of participants (n = 12) were within the intermediate range. Using the binary cut-off of p-tau217 > 0.64 pg/mL for T+, 100% EOAD and 0% other-ND A + participants, defined by the two-tiered cut-off approach, were T + . No associations of p-tau217 with age, sex, or ethnicity were found within ND groups. P-tau217 was elevated in individuals with severely impaired renal function.ConclusionsThe findings support the clinical utility of plasma p-tau217 in the real-world diagnostic evaluation of EOAD. However, careful interpretation of false positive results in patients with severe renal impairment is required.

Keywords: Alzheimer's disease; blood biomarkers; dementia; neurocognitive disorders; young onset dementia.

Figure 1.

Plasma p-tau217 in clinically diagnosed non-neurodegenerative diseases (non-ND), early onset Alzheimer's disease (EOAD) and other neurodegenerative diseases and other dementia (other-ND). (A) Plasma p-tau217 is elevated in EOAD (N = 39), compared with participants with non-ND (N = 52) and other-ND (N = 27) using general linear models, before and after adjusting for age, sex, ethnicity and eGFR. Plasma p-tau217 values were natural logarithm transformed to ensure that the model residuals approximated normal distribution. The error bars represent 95% CI, and the line segment represents the median. The dotted lines represent a previously published plasma p-tau217 intermediate range (0.4 pg/mL – 0.63 pg/mL) for amyloid-β pathology. Plasma p-tau217 concentrations of 12 individuals were within this intermediate range (non-ND = 7, AD = 3, other-ND = 2). NS represents non-significant, and p < 0.05 was considered significant. (B) represents receiver operating characteristic (ROC) curves distinguishing EOAD from non-ND and other-ND.

Figure 2.

EOAD participants positive for tau pathology based on plasma p-tau217. Employing a previously published plasma p-tau217 cut-off >0.64 pg/mL for tau pathology, two non-ND participants appeared tau pathology positive and five EOAD participants appeared tau pathology negative. The dotted line represents p-tau217 = 0.64 pg/mL. T- is represented in blue and T + is represented in red.

Figure 3.

Association of plasma p-tau217 with age, sex, ethnicity and eGFR. (A) Spearman's correlation coefficients were used to assess the association of plasma p-tau217 with age in non-ND (R = 0.302, p = 0.030), EOAD (R = 0.066, p = 0.689) and other-ND (R = 0.215, p = 0.282). (B) Mann-Whitney U tests were used to compare p-tau217 between women (W) and men (M) (p > 0.05), (C) Kruskal-Wallis tests were used to compare p-tau217 between ethnicities (p > 0.05) and (D) between three eGFR ranges, within each diagnostic group. Data on ethnicity and eGFR were only available for 109 and 107 participants, respectively. Blue: Non-ND; Red: EOAD; Purple: Other-ND; O: Oceanian; E: European comprising British, North-West, Southern and Eastern European; A: Asian comprising South-East Asian, North-East Asian, and Southern and Central Asian; PA: People of Americas; SA: Sub-Saharan African. Error bars represent 95% CI and line segments represent the median. p < 0.05 was considered significant.