Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer’s disease

There is an urgent need to improve the understanding of neuroinflammation in Alzheimer’s disease (AD). We analyzed cerebrospinal fluid inflammatory biomarker correlations to brain structural volume and longitudinal cognitive outcomes in the DELCODE study and in a validation cohort of the F.ACE Alzheimer Center Barcelona. We investigated whether respective biomarker changes are evident before onset of cognitive impairment. YKL-40; sTREM2; sAXL; sTyro3; MIF; complement factors C1q, C4, and H; ferritin; and ApoE protein were elevated in pre-dementia subjects with pathological levels of tau or other neurodegeneration markers, demonstrating tight interactions between inflammation and accumulating neurodegeneration even before onset of symptoms. Intriguingly, higher levels of ApoE and soluble TAM receptors sAXL and sTyro3 were related to larger brain structure and stable cognitive outcome at follow-up. Our findings indicate a protective mechanism relevant for intervention strategies aiming to regulate neuroinflammation in subjects with no or subjective symptoms but underlying AD pathology profile. •Neuroinflammation biomarker study on cerebrospinal fluid of DELCODE and F.ACE cohorts•Synchronous pre-dementia elevation of inflammatory, tau, and neurodegeneration markers•Among these, sTyro3 and sAXL positively relate to MRI structure and cognition•Could TAM signaling be protective during pre-dementia neuroinflammation? In the DELCODE and F.ACE cohorts, Brosseron, Maass, Kleineidam, et al. find that inflammatory CSF biomarkers rise in pre-dementia stages alongside tau and neurodegeneration markers. Within this pattern, soluble TAM receptors sTyro3 and sAXL positively relate to MRI structure and cognition, potentially as proxies of immune regulatory protective mechanisms.