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Abstract: Alzheimer’s disease (AD) is a growing public health challenge affecting millions worldwide. It is characterized by the accumulation of beta-amyloid plaques, tau neurofibrillary tangles, and progressive cognitive decline. Autopsy studies suggested that one of the earliest brain regions affected by AD-related tau pathology is the locus coeruleus (LC), a small brainstem nucleus that serves as the brain’s primary source of norepinephrine. Given these observations and the LC’s critical role in cognitive processes disrupted in AD, such as learning and memory, early LC dysfunction has been hypothesized to contribute to AD progression. However, functional neuroimaging of the LC remains challenging due to its small size, proximity to the fourth ventricle, and susceptibility to physiological artifacts and partial volume effects. In this talk, I will introduce a methodological framework to improve the signal-to-noise ratio in LC functional neuroimaging. I will also present findings relating LC dysfunction to AD pathology and cognitive decline in preclinical AD.