Dorsal raphe and locus coeruleus activity shapes depressive and cognitive symptoms in preclinical Alzheimer’s disease

The locus coeruleus (LC) and dorsal raphe nucleus (DR) are among the earliest brain regions to accumulate tau pathology in Alzheimer’s disease (AD) and show topographically specific early rostral vulnerability. As critical modulators of cognitive and affective processes, early dysfunction of these respectively noradrenergic and serotonergic nuclei may contribute to neuropsychiatric symptoms and cognitive decline in preclinical AD. Both nuclei also respond robustly to novelty, a process impaired in early AD, thereby providing a key paradigm to assess how their joint (dys)function relates to these early symptoms. Here, we examined novelty-related fMRI across multiple scales (whole-nuclei, voxelwise, and multivariate cross-nuclei patterns) in association with amyloid and tau positron emission tomography (PET) in 90 cognitively unimpaired older adults to determine whether brainstem (dys)function relates to depressive symptoms or cognitive performance over 7.3±2.9 years. In individuals with elevated amyloid or tau pathology we found topographically-specific associations between nucleus (dys)function and symptomatology. Lower LC activity, particularly in caudal regions, was associated with greater cognitive decline. The DR showed rostro-caudal dissociation: lower rostral activity was associated with faster cognitive decline but less worsening of subthreshold depressive symptoms, while higher caudal activity was associated with steeper cognitive decline. Multivariate analyses captured coordinated patterns of (dys)function across both nuclei that related to cognitive decline. These preliminary findings highlight the complexity of monoaminergic dysfunction in preclinical AD, with differential effects across nuclei, anatomical subregions, and symptom domains. Effective interventions may therefore need to be tailored to an individual’s specific profile of monoaminergic (dys)function.

Recommended citation: Lawn, T., Prokopiou, P. C., Heinrich, L., Donovan, N. J., Papp, K. V., Marshall, G. A., Gatchel, J. R., Rentz, D. M., Johnson, K. A., Sperling, R. A., & Jacobs, H. I. L. (2026). Dorsal raphe and locus coeruleus activity shapes depressive and cognitive symptoms in preclinical Alzheimer’s disease. Under review at Molecular Psychiatry.
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