Plasma Biomarkers of Neurodegeneration and Tau in Relation to Longitudinal Depressive Symptoms in Older Adults: Findings from the Harvard Aging Brain Study

Abstract

AbstractBackgroundDepressive symptoms are common in late life and Alzheimer’s Disease (AD) but the underlying neurobiology of these symptoms and their relationships to AD biomarkers is unclear. Probing these relationships using biomarkers of neurodegeneration and tau that can be measured via plasma can importantly guide AD prognosis and treatment. The current study determined the relationships between baseline measures of neurofilament light (NfL) (a marker of neurodegeneration) and an N‐terminal fragment of tau (NT1, an early and specific marker of AD) and longitudinal depressive symptoms in a cohort of older adults.MethodLongitudinal data were analyzed from 342 participants from the Harvard Aging Brain Study, an observational cohort study of individuals who were cognitively unimpaired and with no/minimal depressive symptoms at baseline (age: 71.7 +/‐ 8.1; % female: 61%; average follow up: 3.94 years, range: 0–7.88). Depressive symptoms were assessed annually with the 30‐item Geriatric Depression Scale (GDS). At study baseline, all participants had plasma samples assayed for NfL and NT1 and underwent amyloid (PiB) PET imaging to derive a cortical amyloid composite. Linear mixed effects models were used to examine relationships between dependent variable longitudinal GDS (log‐transformed) and predictors of interest: (plasma NfL or NT1) x time, and covariates: age, sex, education. Secondary models were adjusted for cortical amyloid and examined the interactive effects of amyloid and plasma biomarkers on longitudinal GDS.ResultHigher baseline NfL predicted increasing GDS scores over time (β = 0.04 +/‐0.01, t = 3.8, p = 0.0001), while a trend was observed for NT1 (β = 0.02 +/‐0.01, t = 1.9, p = 0.06). Similar results were obtained when adjusting models for amyloid x time (NfL x time: β = 0.04 +/‐0.01, t = 3.8, p = 0.0002; NT1 x time: β = 0.02 +/‐0.01, t = 1.7, p = 0.09). Neither NfL nor NT1 interacted with amyloid to predict increasing GDS over time.ConclusionFindings support an association between depressive symptoms and plasma measures of neurodegeneration–whether cause or consequence. Moreover, for NfL, this relationship is independent of amyloid, suggesting that multiple pathways may underlie the emergence of depressive symptoms in older adults. Further longitudinal investigation in relation to cognition and across depressive symptom severity is needed to better understand the pathophysiology of depression in late life and AD.