Late-Life Mood Disorders Show Strong Association with Tau and Amyloid Pathology, Study Reveals
Authors say their findings support the accumulating evidence that late-life mood disorders may be a prodromal manifestation of dementia vs a risk factor alone.
A comprehensive study using advanced brain imaging and postmortem analysis has revealed that approximately 50% of adults with late-life mood disorders (LLMDs) demonstrate tau accumulation in their brains, compared to only 15% of healthy controls, suggesting these psychiatric conditions may serve as prodromal indicators of neurodegenerative diseases including Alzheimer disease (AD).1
The research, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association on June 9, 2025, examined 52 participants with LLMDs and 47 healthy controls using positron emission tomography (PET) imaging with 2 commonly used tracers. The study team, led by and Keisuke Takahata, MD, PhD and PhD student Shin Kurose, from the National Institutes for Quantum Science and Technology (QST), Japan, also analyzed brain tissue samples from 208 autopsy cases to validate their neuroimaging findings.1
The PET imaging revealed that 28.8% of LLMD participants showed detectable amyloid deposits versus only 2% of controls. When stratified by condition, 60% of participants with late-life depression and 40.5% of those with late-life bipolar disorder demonstrated tau accumulation. For amyloid beta (Aβ) pathology, 36% of participants with depression and 22% of those with bipolar disorder showed positive findings, according to the study.1
Autopsy analysis corroborated these results, demonstrating a higher prevalence of diverse tau protein-related pathologies in individuals who had experienced late-life mania or depression. According to Takahata et al, tau accumulation was concentrated in frontal brain regions, areas crucial for emotional regulation and cognitive function. Notably, mood symptoms preceded dementia-associated cognitive or motor symptoms by an average of 7.3 years in the postmortem cases.1
A significant portion of patients with late-life mood disorders were positive for tau and amyloid accumulation in their brains, suggesting these conditions could be early warning signs for neurodegenerative pathologies like AD.
“Because most of the participants with LLMDs in our study had no or mild cognitive decline, these results support the evidence that neurodegenerative diseases, including [Alzheimer] and non-[Alzheimer] tau-related pathologies, can initially manifest as psychiatric symptoms,” Kurose said in a statement.2
The study included adults currently experiencing mood episodes and those in remission. At the time of PET scanning, 23 participants were in remission, 28 were experiencing depression, and 1 was experiencing mania. The prevalence of tau and Aβ pathology remained similar between participants with active symptoms (51.7% and 31%, respectively) and those in remission (47.8% and 26.1%, respectively).1
Takahata and colleagues emphasized the diagnostic implications, noting that the findings suggest that tau-PET scans are valuable tools to detect a range of tau pathologies that potentially underlie dementia in adults with LLMDs.1
Biologic Connections Unclear
The research addresses a significant knowledge gap in understanding the biological connections between LLMDs and neurodegenerative diseases. While there is published evidence for associations between late-life depression and AD, neurologic mechanisms remained unclear, particularly for late-life bipolar disorder, which has received limited investigation in relation to dementia risk.3
For the study, Takahata, Kurose and colleagues examined adults who first experienced depression or mania after age 40 and had no cognitive impairment at the time. The primary study objective was to determine frequency and types of AD and non-AD tau pathologies in living adults compared to age- and sex-matched healthy controls.1
These findings carry clinical implications for the evaluation and management of late-life mood disorders. The researchers suggest that the tracer molecules used during PET may be effective biomarkers for identifying individuals who might benefit from disease-modifying treatments targeting tau pathologies. The ability to detect these abnormal proteins years before traditional cognitive symptoms emerge may enable earlier intervention strategies.1
Takahata, Kurose, et al conclude that "future research should focus on longitudinal imaging and pathological correlations to refine diagnostic and therapeutic approaches for LLMD patients."1
