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. 2025 Jul;21(7):e70434.
doi: 10.1002/alz.70434.

Locus coeruleus integrity correlates with plasma soluble Axl levels in Alzheimer's disease patients

Alessandro Galgani  1 , Arnaud Mary  2 , Francesco Lombardo  3 , Nicola Martini  3 , Marco Scotto  1   4 , Gloria Tognoni  5 , Gabriele Siciliano  5 , Roberto Ceravolo  5 , Filippo S Giorgi  1   6 , Michael T Heneka  2   7
Affiliations

Locus coeruleus integrity correlates with plasma soluble Axl levels in Alzheimer's disease patients

Alessandro Galgani et al. Alzheimers Dement. 2025 Jul.

Abstract

Introduction: Locus coeruleus (LC) is one of the earliest structures altered in Alzheimer's disease (AD). Inflammation is also now considered critical in AD pathology, early stage included. However, no association between LC degeneration and the peripheral inflammation has been reported yet.

Methods: A cohort of 102 patients was studied for which both magnetic resonance imaging (MRI) scans and blood samples were available. LC integrity was assessed by MRI, and plasma soluble TAMs (Tyro3, Axl, and MerTK) receptor levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results: We found that plasma levels of the soluble TAMs receptor Axl were correlated with LC rostral degeneration in the whole cohort (p = 0.007), as well as in the AD+ group (p = 0.017), but not in the AD- group.

Discussion: These results uncover a new relationship between peripheric markers of inflammation and central early AD neurodegeneration.

Highlights: In Alzheimer's disease, no link between locus coeruleus degeneration and microglial activation was reported. Plasma Axl, Tyro3, and MerTK levels and locus coeruleus integrity were assessed in Alzheimer's disease patients. Locus coeruleus integrity positively correlates with plasma AXL, linked to microglia activation. Axl-noradrenergic signaling interplay deserves further larger longitudinal studies.

Keywords: Alzheimer's disease; blood‐based biomarkers; locus coeruleus; neuroinflammation; noradrenaline.

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Conflict of interest statement

The authors report no competing interests.

Figures

FIGURE 1
FIGURE 1
LCCR across diagnostic groups. Scatter plot of LCCR parameter in the three diagnostic groups (HC, MCI, and ADD), considering the entire LC and its two rostral and caudal subregions. Trend lines represent median and interquartile range. Nonparametric tests were used. ADD, Alzheimer's disease dementia; HC, healthy control; LC, locus coeruleus; LCCR, locus coeruleus contrast‐ratio; MCI, mild cognitively impaired.
FIGURE 2
FIGURE 2
TAM receptors plasma levels. Plots representing the levels of sTyro3 (A), sAxl (B), and sMerTK (B) receptors in the plasma of heathy controls (HCs), mild cognitive impairment (MCI), and Alzheimer's disease dementia (ADD) patients (ng/mL). Data are presented as mean ± SEM. p values were calculated using a Kruskal‐Wallis test. ns, non‐significant. sAxl, soluble Axl; sMerTK, soluble MerTK; sTyro3, soluble Tyro3; TAM, Tyro3, Axl, and MerTK.
FIGURE 3
FIGURE 3
Correlation between LCCR and sAxl levels in AD+ patients. Dot plots report the direct correlation between the integrity of rostral LC and plasmatic level of sAxl receptor, in the whole cohort (A) and when subdividing this latter into AD+/AD‐ (HC) subjects (B1‐2), or into mild cognitive impairment (MCI) and Alzheimer's disease dementia (ADD) patients (C1‐2). ρ and p values were obtained using Spearman's correlation test.
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