Atrophy links lower novelty-related locus coeruleus connectivity to cognitive decline in preclinical AD

INTRODUCTION: Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC-MTL functional connectivity (FC _LC-MTL) on cortical atrophy across Braak stage regions and its impact on cognition. METHODS: We analyzed functional magnetic resonance imaging and amyloid beta (Aβ) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FC _LC-MTL with longitudinal atrophy and cognition with and without Aβ moderation. RESULTS: Cross-sectionally, lower FC _LC-MTL was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FC _LC-MTL at elevated levels of Aβ, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FC _LC-MTL and subsequent cognitive decline. DISCUSSION: FC _LC-MTL is implicated in Aβ-related cortical atrophy, suggesting that LC-MTL connectivity could confer neuroprotective effects in preclinical AD. Highlights: Novelty-related functional magnetic resonance imaging (fMRI) LC-medial temporal lobe (MTL) connectivity links to longitudinal Aβ-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aβ burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity–cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.