Relationship Between Indices of CSF HPA AXIS Activity and AD Biomarkers in Late Life Depression

Abstract

Depression is associated with increased risk for Alzheimer's disease (AD), but the mechanisms for this association remain unclear. In preclinical experiments and human studies in Mild Cognitive Impairment (MCI) and AD, increased Hypothalamic-pituitary-adrenal (HPA) axis activity and elevations in CRF or cortisol levels have been strongly associated with increased brain amyloid β (Aβ) and tau pathology burden. Thus, It has been suggested that increased HPA axis activity associated with depression may provide a potential mechanism for its link to AD. However, increased HPA activity in depression is inconsistent and many elderly depressives actually have decreased rather than increased HPA activity; therefore, it is unclear if HPA activity plays a role in the modulation of AD biomarkers and AD risk in this population. To evaluate this hypothesis, we examined the relationship between CSF indices of HPA axis activity (CRF, cortisol), and biomarkers of AD or brain amyloid burden (Aβ42, Aβ40), neurodegeneration (total-tau), tauopathy (p-tau) in cognitively intact individuals with late-life Major Depression (LLMD) and controls. CSF was obtained from 47 older, 28 with LLMD and 19 healthy controls. All were 60 or older with an MMSE score of at least 28 and without significant MRI white matter hyperintensities. CSF AD biomarkers were determined at baseline. Spearman's correlations were calculated to examine associations between CSF indices of HPA axis activity and CSF AD biomarkers. Neither CSF cortisol nor CRF levels were significantly different across groups. In controls, neither cortisol nor CRF significantly correlated with any of the AD biomarkers examined. In contrast, when participants with LLMD were examined, cortisol was found to be positively associated with t- and p-tau levels (rho=0.477 and rho=0.417, respectively). CRF did not significantly correlate with any variable in this sample. Our results suggest that in depressed elderly, increased basal concentration of morning CSF cortisol levels, which may reflect heightened HPA axis activation, is linked to increased total and phosphorylated tau. In contrast, CSF Aβ levels, which are typically thought to contribute to the link between depression and AD, did not correlate with indices of HPA-axis activation.