Locus Coeruleus Connectivity Confers Cognitive Resilience in Preclinical Alzheimer’s Disease
Published in Submitted, 2026
Some individuals maintain cognitive function despite substantial Alzheimer’s disease (AD) pathology. The structural integrity, activity, and metabolism of the locus coeruleus (LC) have been associated with cognitive resilience. The LC provides widespread neuromodulatory control over networks subserving critical cognitive functions like attention and memory, including the frontoparietal control network that has also previously been associated with resilience. However, whether the LC’s protective effects on cognition are conferred through its modulation of these large-scale brain networks remains untested. Here, we examined 393 cognitively unimpaired, amyloid-positive individuals from the A4 study using linear mixed-effects models to investigate whether seed-based LC functional connectivity (LC-FC) moderates amyloid-related cognitive decline. Higher baseline LC-FC was associated with attenuated cognitive decline over 5.5 years, driven primarily by connectivity to frontoparietal control, attentional, and somatomotor networks. Critically, this protection was most pronounced in individuals with greater amyloid burden, ε4+ carriers, and particularly female ε4+ carriers. These findings suggest that LC-mediated cognitive resilience operates through modulation of distributed brain networks and indicate that noradrenergic interventions may be most beneficial when targeted to high-risk individuals exhibiting lower LC connectivity.
Recommended citation: Lawn, T., Diez, I., Bueichekú, E., Coughlan, G., Rentz, D. M., Johnson, K. A., Sperling, R. A., Sepulcre, J., & Jacobs, H. I. L. (2026). Locus Coeruleus Connectivity Confers Cognitive Resilience in Preclinical Alzheimer’s Disease. Submitted.
Download Paper