Abstract
<title>Abstract</title> <p> Dementia with Lewy bodies (DLB) is characterized by marked biological heterogeneity, only partly explained by the frequent presence of Alzheimer’s disease (AD) copathology. Whether microglial responses contribute to this heterogeneity and how they are modulated by APOE genotype remain poorly understood. Using a specific immunoassay targeting cleaved soluble TREM2 (sTREM2), we investigated TREM2-dependent microglial responses across two independent DLB cohorts (n = 129) with molecular biomarker profiling and longitudinal follow-up. sTREM2 showed stage-dependent associations with AD-related biomarkers, being associated with amyloid-related changes during prodromal DLB and predominantly to tau-related markers at dementia stage. <italic>APOEε4</italic> carriers exhibited approximately two-fold lower sTREM2 levels than non-carriers specifically during prodromal DLB, independently of AD copathology, with more pronounced effects observed in women. Longitudinal analyses showed that higher baseline sTREM2 levels during prodromal DLB were associated with slower cognitive decline independently of AD-related biomarkers. These findings suggest that <italic>APOEε4</italic> attenuates early TREM2-mediated microglial responses in DLB through mechanisms beyond AD copathology. Together, our results identify the APOE–TREM2 axis as a potential contributor to disease heterogeneity and support stage-specific, biomarker-guided therapeutic strategies targeting TREM2 signaling in Lewy body disorders. </p>