Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease

Wearn, A.; Onuska, K. M.; Shanks, H. R. C.; Gaurav, R.; Lehericy, S.; Baracchini, G.; Hughes, C.; Tremblay-Mercier, J.; Narayanan, S.; Breitner, J.; Poirier, J.; Schmitz, T. W.; Turner, G. R.; Spreng, R. N.; PREVENT-AD Research Group,

doi:10.64898/2025.12.02.691923

bioRxiv · 10.64898/2025.12.02.691923

Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease

Wearn, A.·Onuska, K. M.·Shanks, H. R. C.·Gaurav, R.·Lehericy, S.·Baracchini, G.·Hughes, C.·Tremblay-Mercier, J.·Narayanan, S.·Breitner, J.·Poirier, J.·Schmitz, T. W.·Turner, G. R.·Spreng, R. N.·PREVENT-AD Research Group,

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Abstract

INTRODUCTIONThe locus coeruleus (LC) is among the first sites of tau pathology in Alzheimers disease (AD) and may seed neocortical tau. METHODSWe used longitudinal neuromelanin-sensitive MRI to assess LC integrity in vivo in a cohort of cognitively unimpaired older adults with familial risk of AD in relation to tau and amyloid PET and long-term cognitive trajectories. RESULTSWe showed that both LC integrity at baseline and its rate of degeneration over time independently predicted a neocortical pattern of tau deposition. In keeping with the known function of the LC, neuropsychological tests showed that LC integrity at baseline predicted changes in attention. Finally, we found that longitudinal LC degeneration correlated with memory decline in people with elevated neocortical amyloid burden. DISCUSSIONOur findings underscore the importance of LC in AD pathogenesis. Longitudinal measurement of LC degeneration may help distinguish trajectories of age-related cognitive decline and early AD.

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Wearn, A., Onuska, K. M., Shanks, H. R. C., Gaurav, R., Lehericy, S., Baracchini, G., Hughes, C., Tremblay-Mercier, J., Narayanan, S., Breitner, J., Poirier, J., Schmitz, T. W., Turner, G. R., Spreng, R. N., PREVENT-AD Research Group,. 2025-12-05. Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease. https://doi.org/10.64898/2025.12.02.691923

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