Clinical value of plasma ALZpath pTau217 immunoassay for assessing mild cognitive impairment

Abstract

Background: Among plasma biomarkers for Alzheimer's disease (AD), pTau181 and pTau217 are the most promising. However, transition from research to routine clinical use will require confirmation of clinical performance in prospective cohorts and evaluation of cofounding factors.

Method: pTau181 and pTau217 were quantified using, Quanterix and ALZpath, SIMOA assays in the well-characterised prospective multicentre BALTAZAR (Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk) cohort of participants with mild cognitive impairment (MCI).

Results: Among participants with MCI, 55% were Aβ+ and 29% developed dementia due to AD. pTau181 and pTau217 were higher in the Aβ+ population with fold change of 1.5 and 2.7, respectively. MCI that converted to AD also had higher levels than non-converters, with HRs of 1.38 (1.26 to 1.51) for pTau181 compared with 8.22 (5.45 to 12.39) for pTau217. The area under the curve for predicting Aβ+ was 0.783 (95% CI 0.721 to 0.836; cut-point 2.75 pg/mL) for pTau181 and 0.914 (95% CI 0.868 to 0.948; cut-point 0.44 pg/mL) for pTau217. The high predictive power of pTau217 was not improved by adding age, sex and apolipoprotein E ε4 (APOEε4) status, in a logistic model. Age, APOEε4 and renal dysfunction were associated with pTau levels, but the clinical performance of pTau217 was only marginally altered by these factors. Using a two cut-point approach, a 95% positive predictive value for Aβ+ corresponded to pTau217 >0.8 pg/mL and a 95% negative predictive value at <0.23 pg/mL. At these two cut-points, the percentages of MCI conversion were 56.8% and 9.7%, respectively, while the annual rates of decline in Mini-Mental State Examination were -2.32 versus -0.65.

Conclusions: Plasma pTau217 and pTau181 both correlate with AD, but the fold change in pTau217 makes it better to diagnose cerebral amyloidosis, and predict cognitive decline and conversion to AD dementia.

Keywords: ALZHEIMER'S DISEASE.

Figure 1. Plasma pTau217 and pTau181 in mild cognitive impairment according to amyloid status. Distribution of (A) pTau217 and (B) pTau181 in pg/mL is represented in the Aβ− and Aβ+ populations. (C) Receiving operator characteristic curves for the same data. Both biomarkers were significantly different between these two populations and a logistic regression model combining pTau values with age, sex and APOEε4 status gave slightly higher AUCs. (D) Area under the curve (AUC) with 95% CIs.

Figure 2. Conversion to Alzheimer’s disease (AD) dementia and Mini-Mental State Examination (MMSE) evolution according to pTau181 or pTau217 tertiles. Plasma pTau217 and pTau181 measurements were separated into tertiles and conversion to AD dementia determined at 6-month intervals over 3 years (panels A, B). A very significant overall difference was observed for both pTau217 and pTau181 (Log-rank test (overall difference) 76.1 and 46.7, respectively, both p <0.0001). HR between first versus third tertile was 7.37 (4.86 to 11.16) compared with just 3.83 (2.54 to 5.79) for plasma pTau217 and pTau181, respectively. The average slopes of MMSE decline per year in pTau terciles are plotted in panels C, D. Grey shadows show the CI. Lower lines show increasing tertile: first tertiles are green, second tertiles, blue and third tertiles are orange.

Figure 3. Association of plasma pTau217 and pTau181 levels with different biomarkers and cohort characteristics Forest plots of associations between demographic (panel A) and comorbidity (panel B) biomarkers and plasma pTau217(red) or pTau181(blue), using linear regression of z-scores. Means and 95% CIs are provided. The concentrations of plasma pTau217 (panel C) or pTau181(panel D), in Aβ− (orange) and Aβ+ (blue) participants, are represented in participants stratified by their estimated glomerular filtration rate (eGFR) (eGFR ≤60: impaired renal function; 60–90 mildly reduced renal function, >90 normal renal function). The value corresponding to the optimal cut-points for Aβ+ detection (Youden index) in all the population is represented by a dotted line. Note that the line separates the Aβ− and Aβ+ population for pTau217 only. APOE, apolipoprotein E; BMI, body mass index; CRP, C reactive protein; HDL, high-density lipoproteins; LDL, low-density lipoproteins; TSH, thyroid stimulating hormone.