A new longitudinal analysis suggests that in older adults without memory problems, the buildup of Alzheimer’s-related tau protein in the brain tends to precede a rise in mild depressive symptoms, implying mood changes may be an early consequence of brain changes rather than a trigger for disease progression. The findings, published in the Journal of Neuroscience, indicate that subtle late-life mood shifts may reflect underlying pathology in cognitively healthy individuals, offering a potential window for early observation of Alzheimer’s-related brain changes.
Alzheimer’s disease is characterised biologically by the accumulation of amyloid-beta plaques outside brain cells and misfolded tau tangles inside neurons. Long before memory problems are evident, individuals often experience mood changes such as apathy, anxiety or mild depression, a pattern researchers have long noted but not fully understood in terms of cause and effect.
In particular, the study addresses the question of whether depressive symptoms drive tau spread or vice versa. While both processes intensify together, the researchers sought to disentangle the directionality, given the possibility that early tau damage could disrupt mood-regulating circuits or that mood disturbances might influence neural vulnerability to tau.
Earlier work, including a 2017 pilot study in cognitively normal older adults, linked higher tau burden in memory-related brain regions with more depressive symptoms at a single point in time, but could not establish causality or the sequence of changes.
In the latest analysis, Teodora Z. Markova and Anne S. Berry, with co-author Margo B. Heston, re-examined large-scale data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to explore the temporal dynamics between tau accumulation and depressive symptoms over several years.
“Most of the work thus far in the field was correlational, just showing associations between more tau pathology and worsening depressive symptoms,” study lead author Markova explained. “I wanted to leverage existing large-scale datasets like ADNI to really try and understand the dynamics between the two variables. While it’s hard to establish any ‘causal’ relationships with this kind of data, I wanted to use some creative statistical approaches to better understand which variable changes first, and get a better sense of whether tau accumulates before mood worsens (tau ‘causing’ disruptions in mood) or vice versa.”
The team analysed records from 390 older adults enrolled in ADNI, including 197 women and 193 men. At baseline, 226 participants had normal cognition, while 164 had mild cognitive impairment or Alzheimer’s dementia. None had clinical depression at the start, scoring 6 or lower on the 15-point Geriatric Depression Scale.
Over an average follow-up of about three years, participants underwent at least two PET scans to measure tau, along with repeated mood questionnaires and memory tests. Tau imaging involved injecting a tracer that binds to tau tangles, enabling researchers to quantify buildup in different brain regions over time.
To tailor the analysis, the researchers tracked tau progression using the most advanced region already crossing the tau-positivity threshold for each participant, and they accounted for amyloid-beta plaques and the APOE ε4 gene variant, a major genetic risk factor for late-onset Alzheimer’s. Full statistical outputs were made publicly available on the Open Science Framework.
As expected, those in the cognitively impaired group started with higher tau levels and more depressive symptoms, and both measures rose faster than in the cognitively normal group. On the mood scale, the cognitively normal group averaged 0.8, compared with 2.1 in the impaired group, while amyloid or APOE ε4 carriage was linked to higher starting tau but did not significantly alter starting depression scores or their change over time.
When testing how tau and mood changes related over time, a pattern emerged in the cognitively normal group that ran contrary to the researchers’ initial two-way loop prediction. Faster tau rise was associated with steeper increases in depressive symptoms, but the reverse — faster worsening of mood predicting faster tau accumulation — was not statistically significant.
A straightforward test for whether starting tau predicted later mood changes, or the reverse, yielded no significant results in either group. The researchers then applied continuous time structural equation modelling, which estimates how changing variables predict future values across irregular visit intervals. This approach required excluding some participants whose depression scores remained flat over time.
Among 131 cognitively healthy individuals with mood changes, higher tau at a given scan predicted higher depressive symptoms at later visits, though the team notes that the strength of this link varied with the number of measurements. Once again, the reverse pathway was not statistically significant. In the cognitively impaired group, neither direction reached statistical significance. To verify their modelling, the researchers repeated the test using memory scores instead of mood and observed the expected result: higher tau predicted subsequent memory decline in both groups.
The researchers also estimated the age at which each participant first crossed tau positivity in the entorhinal cortex, one of the earliest regions to develop tau tangles. Among those with at least one tau-positive scan, the cognitively impaired group reached positivity at an average age of 67.6, about four and a half years earlier than the cognitively normal group’s average onset age of 72.2. In the normal group, longer duration of tau positivity related to steeper increases in depressive symptoms, whereas this relationship was not statistically significant in the impaired group.
Markova admitted she was surprised by the finding that significant tau–depressive symptom effects appeared only in the cognitively unimpaired sample, not in the MCI or dementia group, highlighting the complexity of conditions once a diagnosis is established. She emphasised that different approaches may be required to understand dynamics in later disease stages.
She framed the broader takeaway for readers: late-life mood changes can be informative about evolving brain pathology. “A significant change in mood or a new neuropsychiatric symptom in later life could offer meaningful information about what’s going on in your brain,” she said, noting that mood shifts should be considered alongside other biomarkers when assessing Alzheimer’s risk.
Another key point is the demonstrated value of tau PET imaging, despite the small and subtle effects observed. “Although the effects are small, we are still able to track significant relationships with tau PET imaging,” Markova added, underscoring the technique’s potential in monitoring disease processes alongside mood changes.
The study authors caution that the analyses are observational and timing estimates are rough, given the typical two to three scans per participant. They also note that the mood findings rely on self-reported measures and may not be directly extrapolated to those with clinical depression. In later stages of disease, mood reporting becomes less reliable as memory and thinking decline, and broader brain changes may overshadow tau’s role.
Looking ahead, the researchers call for longer-term follow-up across more diverse populations and the inclusion of caregiver assessments, smartphone mood check-ins, and wearable sleep data to map emotional health and brain biology across the full course of aging. The study is titled Tracking the Continuous Time Dynamics of Tau and Depressive Symptoms Across the Alzheimer’s Disease Continuum and was authored by Teodora Z. Markova, Margo B. Heston, and Anne S. Berry.
