LOCUS COERULEUS STRUCTURAL INTEGRITY IS ASSOCIATED WITH CIRCULATING SOLUBLE AXL IN ALZHEIMER’S DISEASE

Galgani A¹, Scotto M², Mary A³, Lombardo F⁴, Martini N⁴, Siciliano G⁵, Ceravolo R⁵, Heneka MT^3,6 and Giorgi FS^1,7 | ¹Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy; ²Laboratory of Medical Science, Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy; ³Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg; ⁴Department of Radiology, Fondazione Toscana “G. Monasterio”, Pisa, Italy; ⁵Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; ⁶Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA; ⁷I.R.C.C.S. Stella Maris, Calambrone, Pisa, Italy

The locus coeruleus (LC) is among the earliest brain regions affected in Alzheimer’s disease (AD), exhibiting neuronal loss and accumulation of hyperphosphorylated tau decades before the onset of symptoms. At the same time, growing evidence highlights neuroinflammation as a central contributor to AD pathogenesis, even at prodromal stages. The TAM (Tyro3, Axl, and MerTK) receptor family plays a crucial role in regulating immune homeostasis and inflammatory signaling. However, a potential link between LC degeneration and peripheral inflammatory markers has not been demonstrated to date. We studied a cohort of 102 participants for whom both high-resolution MRI and blood samples were available. LC integrity was quantified using MRI-based contrast measures of LC signal intensity, focusing on rostral and caudal subregions. Plasma concentrations of soluble TAM receptors (Tyro3, Axl, and MerTK) were determined by enzyme-linked immunosorbent assay (ELISA). Participants were stratified into AD⁺ (amyloid- positive) and AD^– groups based on clinical and biomarker criteria. Across the entire cohort, plasma soluble Axl (sAxl) levels showed a significant negative correlation with rostral LC integrity (p=0.007), indicating that higher circulating sAxl levels are associated with more pronounced LC degeneration. This relationship remained significant within the AD⁺ group (p=0.017) but not in the AD– group, suggesting a disease-specific association. No significant correlations were observed for Tyro3 or MerTK. Our findings identify a novel association between peripheral soluble Axl levels and central noradrenergic degeneration in AD. This is the first time, to our knowledge, that an in vivo link between neuroinflammation and LC degeneration has been detected in patients. These results provide new insight into the interplay between immune activation and early brainstem vulnerability in Alzheimer’s disease and may pave the way toward new therapeutic targets.