Tracking the Continuous Time Dynamics of Tau and Depressive Symptoms Across the Alzheimer’s Disease Continuum

In aging and Alzheimer’s disease (AD), higher levels of tau pathology often coincide with an increased number of depressive symptoms. To establish probable causality between tau accumulation and depressive symptom trajectories, we applied three complementary analysis approaches using longitudinal positron emission tomography ([18F]flortaucipir) and Geriatric Depression Scale (GDS) data in male and female humans from the Alzheimer’s Disease Neuroimaging Initiative. Participants were not clinically depressed at baseline and were categorized as cognitively normal (CN) or cognitively impaired (mild cognitive impairment (MCI)/AD dementia). Linear mixed effects models revealed rates of tau accumulation significantly moderated how quickly depressive symptoms increased over time in the CN sample, while GDS slopes did not moderate tau accumulation. We used continuous time structural equation modeling to test directionality and found that, in the CN sample, greater tau predicted higher subsequent GDS, while variability in GDS did not predict later tau. Finally, we tested the hypothesis that, if tau drives increasing depressive symptoms, the onset of tau positivity would be accompanied by worsening depressive trajectories. In the CN sample, longer duration of tau positivity was associated with steeper increases in GDS scores. No significant results were observed in the MCI/AD dementia sample, suggesting the unique value of early temporal windows for disentangling how affective and neuropathological changes contribute to disease progression. Together, these findings support a model by which early tau deposition in cognitively unimpaired older adults likely contributes to the emergence of depressive symptoms, while depressive symptoms exert little influence on tau at this stage. Significance statement Subtle changes in depressive symptoms in cognitively normal older adults track with tau accumulation. However, it is unclear whether subclinical affective changes are an early symptom of underlying neuropathology, or are a risk factor for the development of AD. We aimed to establish a temporal ordering of tau accumulation and depressive symptom trajectories to better understand the development of neuropsychiatric symptoms. Our longitudinal analyses show that tau accumulation precedes changes in Geriatric Depression Scale scores, providing evidence that subtle affective changes may emerge as a consequence of early pathology. Monitoring depressive trajectories could therefore offer valuable complementary information to other clinical and biomarker measures when evaluating risk for developing neurodegenerative disease, helping to increase the potential for early AD detection.