Imaging the locus coeruleus–glymphatic axis in Alzheimer’s disease: From neuromelanin MRI to DTI-ALPS

Alzheimer’s disease (AD) is increasingly recognized as a disorder not only of cortical amyloid-β and tau deposition, but also of upstream neuromodulatory and clearance systems that shape when and where pathology emerges. Among these, the locus coeruleus (LC) noradrenergic nucleus and the brain’s perivascular “glymphatic” network have attracted particular attention. In this review, we synthesize converging evidence that positions the LC–glymphatic interplay as a mechanistically relevant “axis” in AD, and evaluate two magnetic resonance imaging (MRI)-based proxies of this axis: neuromelanin-sensitive LC imaging and diffusion tensor image analysis along the perivascular space (DTI-ALPS). We first summarize neuropathological and experimental data demonstrating that the LC is an early and vulnerable tau node whose degeneration perturbs synaptic plasticity, neuroinflammation, sleep–wake regulation and vascular dynamics. The evidence base spans post-mortem neuropathology, animal mechanistic studies, and predominantly cross-sectional human MRI/PET observational cohorts, with fewer longitudinal studies and very limited interventional imaging datasets. We then review acquisition protocols, reliability and clinical findings for LC neuromelanin MRI, highlighting robust associations with cognitive performance and downstream tau burden. In parallel, we describe the physiological basis and methodological implementation of DTI-ALPS as an indirect marker of perivascular CSF–interstitial fluid transport, and collate studies linking reduced ALPS indices to amyloid/tau biomarkers, small vessel disease and cognitive decline. Integrating these literatures, we propose an in-vivo “LC–glymphatic axis” framework in which LC degeneration and impaired perivascular transport co-evolve and jointly influence AD risk and progression. We discuss how this framework can inform biomarker development, risk stratification and trial enrichment, and outline neuromodulatory strategies—such as transcutaneous vagus nerve stimulation and closed-loop slow-wave sleep enhancement—that could be used to experimentally engage this axis with LC MRI and ALPS as mechanism-proximal endpoints. Finally, we critically appraise methodological limitations, conceptual uncertainties and key gaps in longitudinal, multimodal and interventional evidence. Overall, imaging the LC–glymphatic axis offers a promising route to move beyond purely cortical markers and to test whether targeting upstream neuromodulation and clearance can contribute to genuine disease modification in AD.