Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults

Abstract

Introduction: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown.

Methods: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI.

Results: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI.

Discussion: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

Keywords: Alzheimer's disease; amyloid positron emission tomography; cognition; cognitively unimpaired; glial fibrillary acidic protein; medial temporal lobe; neurofilament light; phosphorylated tau217; plasma biomarkers; sex differences; verbal memory.

FIGURE 1

Plasma biomarker concentrations and intercorrelations by sex and clinical status. Box plots represent median, interquartile range, minimum, and maximum (A–C). Sex differences by clinical status are annotated with Cohen d estimates of effect size and P‐values. Pairwise Pearson r correlations with 95% confidence interval are plotted by sex and clinical status (D). CU, cognitively unimpaired; GFAP, glial fibrillary acidic protein; MCI, mild cognitive impairment; NfL, neurofilament light; p‐tau217; phosphorylated tau 217.

FIGURE 2

Plasma p‐tau217 prediction of verbal memory and medial temporal lobe trajectories in CU males (A, D) and females (B, E). For visualization purposes, stratified lines represent the estimated slope of time at the median of each baseline plasma p‐tau217 quartile (pg/ml; Q1 median [range]: 0.041 [0.020 to 0.046]; Q2 median [range]: 0.051 [> 0.046 to 0.068]; Q3 median [range]: 0.078 [> 0.068 to 0.092]; Q4 median [range]: 0.120 [> 0.092 to 0.200]). The effect size (unstandardized) of time on verbal memory z scores (C) and medial temporal lobe volumes (F) is plotted across baseline plasma p‐tau217 in CU females. When the X axis zero‐line is not included in the false discovery rate–adjusted confidence band, the effect of time is statistically significant at that concentration of baseline plasma p‐tau217. The region of significance occurs to the right of the dotted line, indicating that increasing time is significantly associated with worse trajectories once baseline plasma p‐tau217 concentrations surpass 0.053/0.054 pg/ml. CU, cognitively unimpaired; p‐tau217; phosphorylated tau 217.

FIGURE 3

Comparison of sex‐specific plasma biomarker prediction of cognitive and brain volumetric trajectories in cognitively unimpaired adults. Values represent standardized coefficients with bootstrapped 95% confidence intervals for the interaction of baseline plasma biomarker levels and time on cognitive (A, C, E) and brain volumetric (B, D, F) outcomes in cognitively unimpaired adults, stratified by sex. Full model estimates and P‐values are presented in Tables S1 and S2 in supporting information. GFAP, glial fibrillary acidic protein; NfL, neurofilament light; p‐tau217; phosphorylated tau 217.

FIGURE 4

Comparison of sex‐specific plasma biomarker prediction of cognitive trajectories in mild cognitive impairment. Values represent standardized coefficients with bootstrapped 95 % confidence intervals for the interaction of baseline plasma biomarker levels and time on cognitive outcomes in mild cognitive impairment, stratified by sex. Full model estimates and P‐values are presented in Table S1 in supporting information. GFAP, glial fibrillary acidic protein; NfL, neurofilament light; p‐tau217; phosphorylated tau 217.

FIGURE 5

Quadratic relationship between plasma p‐tau217 and cortical Aβ burden. Plasma p‐tau217 exhibits a non‐linear relationship with Aβ PET Centiloids such that initial increases in plasma p‐tau217 correspond with steep increases in cortical Aβ burden that plateau well after established Aβ pathology levels. A single curve was plotted across sex given that the quadratic relationship between plasma p‐tau217 and Aβ PET was not moderated by sex. Thresholds for early (12 Centiloids) and established (30 Centiloids) Aβ pathology were estimated to occur at plasma p‐tau217 concentrations of 0.06 pg/ml and 0.09 pg/ml, respectively. Aβ, amyloid beta; CU, cognitively unimpaired; MCI, mild cognitive impairment; PET, positron emission tomography; p‐tau217; phosphorylated tau 217.