748. Tau Pathology Modulates the Association Between Neurodegeneration and Depressive Symptoms in Alzheimer’s Disease

Abstract

Abstract Background The moderating role of tau pathology in the association between neurodegeneration and depression across the Alzheimer’s disease continuum remains insufficiently characterized. Aims & Objectives This study aimed to examine whether tau pathology modifies the relationship between neurodegeneration markers and depressive symptoms in older adults spanning the Alzheimer’s disease continuum. Method A total of 103 older adults were included. Depressive symptoms were assessed using the Cornell Scale for Depression in Dementia (CSDD), Hamilton Depression Rating Scale (HAM-D), and Geriatric Depression Scale Short Version (GDS-SV). Neurodegeneration markers included lateral ventricular volume (LVV), hippocampal volume, gray matter volume, and white matter hyperintensity volume. Tau pathology was evaluated using Braak stage classification and tau PET standardized uptake value ratios (SUVR). Generalized linear models were applied to test interaction effects between neurodegeneration markers and tau pathology, with multiple comparisons controlled using Benjamini-Hochberg false discovery rate correction. Sensitivity analyses employed continuous tau SUVR values. Results A robust interaction between LVV and advanced tau pathology (Braak stage V/VI) was observed, most prominently for self-reported depressive symptoms measured by the GDS-SV. LVV was positively associated with depressive symptoms at lower tau stages, whereas this association attenuated or reversed at more advanced tau stages. Although interactions involving other neurodegeneration markers did not survive strict false discovery rate correction, they demonstrated consistent stage-dependent patterns. Sensitivity analyses using continuous tau SUVR confirmed that significant associations were confined to lower SUVR ranges. Discussion & Conclusions These findings indicate that the relationship between neurodegeneration and depression is stage-dependent and substantially modulated by tau pathology. The prominence of this interaction in self-reported depressive symptoms underscores the importance of considering both proteopathic stage and preserved insight when interpreting affective symptoms across the Alzheimer’s disease continuum.