In the absence of Alzheimer's Disease pathology, PET-measured hippocampal tau is reduced in association with greater depressive symptoms: Could tau PET be sensitive to physiological tau involved in neurogenesis?

Background: Tau Positron Emission Tomography (PET) visualizes hyperphosphorylated tau tangles which, together with Aβ plaques, are hallmark pathologies of Alzheimer's disease (AD). Greater tau, measured by PET or neuropathology, is robustly linked to worse cognition in AD, but associations with mood are less studied. We previously reported an unexpected inverse relationship between depressive symptoms and PET-measured medial temporal tau in individuals without AD. Here, we confirm and extend this finding in an independent cohort. Methods: We analyzed cross-sectional data from 403 Alzheimer's Disease Neuroimaging Initiative participants who underwent flortaucipir (tau) PET, Aβ PET, MRI, and clinical assessments including the Geriatric Depression Scale (GDS). Participants were categorized as Aβ- or Aβ+. Associations between GDS scores and mean hippocampal flortaucipir uptake were assessed using Spearman correlation and multiple regression. Results: In Aβ- individuals ( Conclusions: In the absence of AD pathology, greater severity of depressive symptoms is associated with lower PET-measured hippocampal tau. Because impaired hippocampal neurogenesis is considered a key mechanism in depression, and tau is a normal component of cell division including neurogenesis, this replicated inverse relationship may reflect reduced hippocampal neurogenesis. Whether tau PET can provide a window into this process in humans requires further study.