Association between plasma brain-derived p-tau variants and anxiety phenotypes in older adults

To determine whether distinct anxiety phenotypes (rumination, global anxiety and worry; RAW) are associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease (AD) in older adults.

Cross-sectional observational study.

Participants were 89 older adults aged ≥50 years (mean age 64.3±8.8 years) enrolled in the RAW Brain study (R01 MH108509) in Pittsburgh, Pennsylvania. Anxiety phenotypes were assessed using the Penn State Worry Questionnaire (PWSQ≥50), Rumination Subscale from the Response Style Questionnaire (RSQ>50), and Hamilton Anxiety Rating Scale (HARS>17). Participants were classified as High-RAW if they exceeded established severity thresholds on ≥1 domain; continuous anxiety scores were used for primary analyses. Plasma BD-tau, BD-p-tau181, BD-p-tau217, and BD-p-tau231, and matched non-BD versions were quantified using the NULISAseq™ CNS Panel. Associations between anxiety phenotypes and tau biomarkers were examined using multivariable linear regression adjusted for age, sex, and APOE4 status, with Benjamini-Hochberg false discovery rate correction.

Greater global anxiety was associated with higher plasma BD-p-tau181 (β=0.308, 95% CI [0.003,0.048], p=0.047). This association was also observed categorically (adjusted Cohen's d=0.462, p=0.049). Worry and rumination were not associated with BD-p-tau181, and no anxiety phenotypes were associated with BD-tau, BD-p-tau217, BD-p-tau231, or corresponding non-BD alternatives.

Greater late-life global anxiety, but not worry or rumination, was selectively associated with higher plasma BD-p-tau181. These findings extend epidemiologic evidence linking anxiety to AD risk by identifying a biologically specific blood-based correlate linking anxiety with AD-related p-tau biology. Longitudinal studies incorporating amyloid and tau biomarker confirmation are needed to determine whether anxiety precedes, accompanies, or results from early AD pathophysiology.

1) What is the primary question addressed by this study? -The question addressed by the study must limited to only one sentence. Is late-life anxiety, including rumination, global anxiety, and worry, associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease in older adults? 2) What is the main finding of this study? -The finding must be limited to two sentences. Greater global anxiety, but not worry or rumination, was associated with higher plasma BD-p-tau181 after adjustment for age, sex, and APOE4 status. No associations were observed with other BD-tau variants or with non-BD-tau versions. 3) What is the meaning of the finding? -The meaning of the finding must be limited to one sentence. These findings suggest that global anxiety may be linked to early Alzheimer's disease-related tau biology and support further longitudinal investigation of anxiety as a potential marker of preclinical disease.