Plasma p-Tau217 and Aβ42/Aβ40 mediate the association between minimal depressive symptoms and cognitive impairment

Depression is a recognized risk factor and potential prodromal feature of Alzheimer's disease (AD). While associations between depressive symptoms and AD pathology have been observed using cerebrospinal fluid (CSF) and PET imaging, it remains unclear whether these relationships can be captured by accessible plasma biomarkers, particularly the highly specific phosphorylated tau-217 (p-Tau217). We analyzed 615 participants from Alzheimer's disease Neuroimaging Initiative (ADNI) cohort, of whom 374 had minimal depressive symptoms (MDS). Plasma biomarkers included phosphorylated tau-217 (p-Tau217), amyloid-β 42/40 ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models and mediation analyses were employed to examine associations between MDS, plasma biomarkers (p-Tau217, Aβ42/Aβ40, NfL, and GFAP), and cognitive impairment, with adjustments for age, sex, and APOE ε4 carrier status. Participants with MDS demonstrated significantly elevated plasma p-Tau217 levels (mean difference = 0.105, 95% CI [0.046, 0.163]; P < 0.001) and reduced Aβ42/Aβ40 (mean difference = -0.024, 95% CI [-0.041, -0.006]; P = 0.007) compared with those without MDS. These associations were primarily observed in non-demented individuals and influenced by age, sex, and APOE ε4 status. In mediation analyses, plasma p-Tau217 accounted for 41.57%-42.18% of the association between MDS and cognitive impairment, while Aβ42/Aβ40 mediated 7.13%-8.45% of this relationship. Plasma biomarkers of p-Tau217 and Aβ42/Aβ40 were associated with early depressive symptoms and mediate their associations with cognitive impairment. These findings identify plasma p-Tau217 as a key mediator linking MDS to cognitive impairment, extending evidence from CSF to accessible blood-based biomarkers. This highlights the value of monitoring plasma p-Tau217 and Aβ42/Aβ40 to unravel the pathological basis of depressive symptoms in early AD.