Plasma phosphorylated tau181 predicts cognitive and functional decline

Abstract

Objective: To determine if plasma tau phosphorylated at threonine 181 (p-tau181) distinguishes pathology-confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p-tau181 predicts cognitive and functional decline, and to validate findings in an external cohort.

Methods: Thirty-one neuropathology-confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N = 91) or AD dementia (N = 64), and NC (N = 241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini-Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures. NC (N = 70), MCI (N = 75), and AD dementia (N = 50) cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used as a validation cohort. Plasma p-tau181 was measured using the Quanterix SiMoA HD-X platform.

Results: Plasma p-tau181 differentiated pathology-confirmed AD from NC with negative amyloid PET scans with an AUC of 0.93. A cut point of 3.44 pg/mL (maximum Youden Index) had a sensitivity of 0.77, specificity of 0.96. p-Tau181 values above the cut point were associated with the faster rate of decline in MMSE in AD dementia and MCI and a shorter time to a clinically significant functional decline in all groups. In a subset of MCI cases from ADNI, p-tau181 values above the cut point associated with faster rate of decline in MMSE, and a shorter time to a clinically significant functional decline and conversion to dementia.

Interpretation: Plasma p-tau181 differentiates AD pathology cases from NC with high accuracy. Higher levels of plasma p-tau181 are associated with faster cognitive and functional decline.

Figure 1

Plasma p‐tau181 level as a binary classifier of disease status. Panels on the left (A, C, E) show the distribution of plasma p‐tau181 values among disease group or cognitively normal individuals. Black bars are inserted to show median and interquartile range. Panels on the right (B, D, F) show receiver operator characteristics (ROC) curves showing the area under the curve (AUC) of each disease group compared to cognitively normal individuals without evidence of amyloid deposition on PET imaging. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. ns, non‐significant; PET, Amyloid positron emission tomography; MCI, Mild cognitive impairment; bvFTD, behavioral variant frontotemporal dementia; PPA, primary progressive aphasia; PD, cognitively normal Parkinson's disease; PSP, progressive supranuclear palsy; CBS, corticobasal syndrome; DLB, dementia with Lewy bodies; ALS, amyotrophic lateral sclerosis.

Figure 2

Performance characteristics for cut points of p‐tau181 as a classifier of Alzheimer's disease versus cognitively normal. (A) Cut points of p‐tau181 (pg/mL) and performance characteristics are shown based on a specified criterion. Youden Index = 1‐(sensitivity+specificity). * = Minimum sensitivity set at 0.70. (B) Sensitivity (red) and specificity (blue) are plotted for all cut points. The black bar represents the cut point at the maximum Youden Index (3.44 pg/mL). (C) Distribution of p‐tau181 values and the density of cases in pathology confirmed Alzheimer's disease (Path + AD), and cognitive normal individual without evidence of amyloid deposition on PET imaging. Vertical lines above the x‐axis represent measured p‐tau181 values.

Figure 3

Plasma p‐tau181 cut point predicts rate of change in cognitive testing in mild cognitive impairment and Alzheimer’ disease groups. (A) Effects of p‐tau181 on longitudinal Mini Mental State Examination (MMSE) performance in each disease, assessed with linear mixed effects models adjusting for age, sex, and baseline MMSE. Coefficients (β), standard error (SE), and p‐values for p‐tau181 cut point*time interaction shown, with time in years. (B) Predicted MMSE values with 95% confidence intervals across 4 years of follow up in groups defined as above (red) or below (blue) the p‐tau181 cut point of 3.44 pg/mL in clinically defined normal cognition, mild cognitive impairment (MCI), and Alzheimer's disease.

Figure 4

Plasma p‐tau181 cut point predicts time to clinically significant functional decline in cognitively normal, mild cognitive impairment, and Alzheimer’ disease groups. Effects of p‐tau181 on time to a clinically significant decline in the Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB), equivalent to an increase by 1.5 points or more from baseline, in each disease, assessed with Cox proportional hazards models. Lines represent the proportion of individuals without functional decline over 8 years of follow‐up. Groups are defined as above (red) or below (blue) the p‐tau181 cut point of 3.44 pg/mL in clinically defined normal cognition (A), mild cognitive impairment (MCI, B), and Alzheimer's disease (C). The number at risk is shown at the bottom at 2‐year intervals.

Figure 5

Plasma P‐Tau181 cut point predicts rate of change in cognitive testing, time to functional decline, and time to dementia onset in mild cognitive impairment in the Alzheimer's disease neuroimaging initiative cohort. (A) Effect of p‐tau181 cut point on longitudinal Mini Mental State Examination (MMSE) performance, assessed with linear mixed effects models adjusting for age, sex, and baseline MMSE. Coefficient (β) and p‐values for p‐tau181 cut point*time interaction shown, with time in years. (B) Effect of p‐tau181 cut point on time to a clinically significant decline in the Clinical Dementia Rating Scale Sum of Boxes, (CDR‐SB), equivalent to an increase by 1.5 points or more from baseline, assessed with Cox proportional hazards model. (C) Effect of p‐tau181 cut point on time to conversion to Dementia, assessed with Cox proportional hazards model. Groups are defined as above (red) or below (blue) the p‐tau181 cut point of 3.44 pg/mL.