2026 ECNP Congress

PS02-2263

Changes in locus coeruleus signal intensity and whole-brain functional connectivity in Alzheimer's disease patients

Ruihua Hou — P. Wang, F. Xue, Q. Liu, C.H. Liu, Y. Chen, A. Liu, C. Warren, A. Reid, T. Chen · University of Southampton Faculty of Medicine, Department of Psychiatry, Southampton, United Kingdom

2026 ECNP Congress

Introduction

The locus coeruleus (LC), as the primary source of norepinephrine in the brain, plays a critical and dual role in the early pathogenesis of Alzheimer’s disease (AD). LC degeneration involves not only progressive structural atrophy but also significant, widespread alterations in its functional connectivity (FC) with other brain regions. Understanding these pathological changes is crucial for uncovering the complex mechanisms underlying disease progression and cognitive decline.

Aims

The aim of this study was to utilise neuromelanin-sensitive magnetic resonance imaging (NM-MRI) to accurately investigate LC signal attenuation in AD patients and to analyse the altered whole-brain FC of the LC using resting-state functional magnetic resonance imaging (rs-fMRI).

Methods

We recruited 20 AD patients and 27 age-matched healthy controls (HC). Following rigorous quality control, 19 AD patients and 27 HC were included for NM-MRI, whilst 19 AD patients and 25 HC were analysed for rs-fMRI. Participants underwent scanning on a 3.0T MRI device. LC contrast ratios (LC-CR) were calculated to assess signal intensity. For rs-fMRI, we analysed ROI-wise FC across 142 distinct regions, intra- and inter-network FC using the Yeo-7 functional networks (visual, somatosensory-motor, dorsal attention, ventral attention, subcortical, frontoparietal, and default mode), and voxel-wise FC using predefined bilateral LC seeds. Statistical analyses included independent samples t-tests for LC-CR group differences. FC analyses employed independent samples t-tests (covariates: age, sex, and head motion) with false discovery rate (FDR) correction (Q < 0.01). Network and voxel-wise analyses utilised 5,000 permutations with threshold-free cluster enhancement (TFCE) correction (p < 0.05).

Results

The AD group exhibited significantly lower LC-CR levels (0.146 ± 0.038) compared to the HC group (0.192 ± 0.050) (p = 0.0021). Furthermore, LC signal intensity positively correlated with cognitive performance, significantly associating with Mini-Mental State Examination (r2 = 0.328, p = 0.0103) and Montreal Cognitive Assessment (r2 = 0.331, p = 0.01) scores. Regarding whole-brain FC, 66 of 142 ROIs showed significantly reduced connectivity in AD patients. Network analyses revealed decreased FC within the visual, dorsal attention, ventral attention, and subcortical networks, alongside reduced inter-network FC across 11 specific network pairs. Crucially, voxel-wise analysis uncovered significant lateralised LC dysfunction. The left LC exhibited weakened connectivity with sensorimotor and emotional processing regions, including the Rolandic operculum (T = 6.436). Conversely, the right LC demonstrated disrupted functional links primarily to attention and higher-order cognitive networks, such as the anterior cingulate gyrus (T = 5.376) and superior parietal lobule (T = 5.597).

Conclusions

The findings confirm that AD is characterised by marked LC degeneration, evidenced by a significant signal reduction that correlates strongly with clinical cognitive decline. Widespread disruption within large-scale functional networks highlights the systemic impact of AD pathology. The distinct lateralised patterns of LC FC impairment—where the left LC predominantly influences sensorimotor integration and the right LC modulates attentional networks—reveal highly specialised roles of the noradrenergic system. These results provide novel insights into neural network degeneration, suggesting that lateralised LC functional pathways may offer highly specific biomarkers and promising therapeutic targets for early-stage intervention.

Keywords: AD, LC, FC, neuroimaging, cognitive decline, norepinephrine

References

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