Abstract
The early accumulation of tau pathology in neuromodulator-producing brainstem regions is a hallmark characteristic of early Alzheimer’s disease (AD). Additionally, the late-life emergence of neuropsychiatric symptoms, such as depressive symptoms, is now recognized as one of the earliest changes associated with underlying AD-development, often preceding clinically relevant cognitive declines. Notably, higher levels of tau burden have been associated with worse mood and more depressive symptoms even in otherwise healthy, cognitively unimpaired older adults, indicating that these processes are in play well before disease onset. Given that these early biological and behavioral changes may occur concurrently, understanding the longitudinal dynamics between tau accumulation and depressive symptoms is critical to help better characterize early disease progression. In particular, focusing on changes in brainstem nuclei such as the dorsal raphe nucleus (DRN) - which is one of the first regions to accumulate tau and produces serotonin, a neuromodulator implicated in depression and mood – may help us to better understand these relationships and identify potential targets for early intervention.
Study 1 focuses on establishing the behavioral contributions of tau accumulation in the amygdala. The impact of tau deposition in the amygdala is relatively understudied in cognitively unimpaired (cognitively normal, CN) older adults despite the established role of the amygdala in emotional regulation and experience. Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we investigated relationships among cross-sectional and longitudinal tau ([18F]flortaucipir [FTP] positron emission tomography, PET), changes in depressive symptoms and memory, and amyloid beta (Aβ) and apolipoprotein E (APOE) ε4 status. We also conducted secondary parallel analyses from the Berkeley Aging Cohort Study (BACS). We found that longitudinal increases in depressive symptoms (measured using the Geriatric Depression Scale, GDS) were associated with higher baseline FTP and increasing FTP in the amygdala. Relationships between FTP and depressive symptoms were strongest in APOE ε4 carriers, with moderation effects replicating in BACS. Entorhinal FTP did not show associations with depressive symptoms beyond variance explained by the amygdala but showed some specific associations with memory decline. The findings from Study 1 indicate a strong coupling between tau accumulation and depressive symptoms in APOE ε4 carriers and reinforce the importance of amygdala tau in understanding neuropsychiatric changes in older adults.
Study 2 aims to establish temporal associations between tau accumulation and depressive symptom trajectories. We once again used data from ADNI and applied three complementary analysis approaches using longitudinal PET ([18F]FTP) and GDS data. 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, elevated 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, the findings from Study 2 support a model by which early tau deposition in cognitively unimpaired older adults is a key driver of emerging depressive symptoms, while depressive symptoms exert little influence on tau at this stage.
Finally, Study 3 focuses on the DRN, one of the earliest targets of AD-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18–85 years-old) from the Berkeley Aging Cohort (BACS). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging (MRI), longitudinal changes in self-reported depression symptoms (measured using the GDS), and AD-related tau and Aβ pathology using cross-sectional [18F]FTP and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together the findings from Study 3 reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.
Overall, these studies establish that, in cognitively unimpaired older adults, (1) amygdala tau is associated with worsening depressive trajectories, especially in those with an increased genetic risk for AD, (2) tau accumulation in general seems to drive the worsening of depressive symptoms and not vice versa, and (3) increased serotonin synthesis capacity in the DRN may be signaling worsening aging trajectories in the context of atrophy, tau pathology, and depressive symptoms. Together these results suggest that tau-related changes, alongside individual differences in affective and serotonergic circuits, play a central role in shaping depressive trajectories in aging, highlighting potential early targets for intervention.