APOEε4 attenuates early TREM2-mediated microglial responses and influences disease trajectories in dementia with Lewy bodies
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: 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. APOEε4 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 APOEε4 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.
Source: Research Square
Authors: Estrella Morenas Rodríguez, Pablo Zaragoza-Ballester, Daniel Alcolea, Diana Esteller-Gauxax, Brigitte Nuscher, Sara Chacón, Álex Fernández-León, Íñigo Rodríguez-Baz, Alexandre Bejanin, Elena Vera, Lidia Vaqué-Alcázar, Maria Franquesa-Mullerat, Isabel Sala-Matevera, Kai Schlepckow, Adolfo Gómez-Grande, Sebastián Ruiz Solís, Alberto Lleó, Valle Camacho, Mircea Balasa, Juan Fortea, Christian Haass
Institutions: Research Institute Hospital 12 de Octubre, Hospital Universitario 12 De Octubre, Hospital de Sant Pau, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Ludwig-Maximilians-Universität München, Institut de Recerca Sant Pau, Universitat de Barcelona, German Center for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Dresden, Universitat Autònoma de Barcelona
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: G1075404386, G1183059914, Aplicación de Tomografía de Array (AT) para el estudio sistemático a gran escala del daño sináptico en las demencias neurodegenerativas, The Role of Inflammation and NGF Dysfunction in the Evolution of AlzheimerDisease Pathology in Down syndrome, La estructura cerebral y el metabolismo en la enfermedad de Alzheimer preclínica. Interacciones entre nuevos y viejos biomarcadores, G2686990546, G3559709381, Enfermedad de Alzheimer y síndrome de Down. Estudios multimodales de líquido cefalorraquídeo, resonancia magnética y PET de amiloide, Estudio del trazador de tomografía por emisión de positrones (PET) para Tau [18F]THK-5351 en pacientes con diferentes Taupatías, Utilidad diagnóstica de Aß42 y Aß42/40 en LCR y plasma para detectar amiloidosis cerebral y correlación con marcadores subrogados de producción de ß-amiloide en enf. de Alzheimer, Factores relacionados con la activación microglial dependiente de TREM2 en la demencia con cuerpos de Lewy, influencia sobre su evolución y aplicaciones clínicas., Estudios longitudinales de RM magnética estructural, de difusión y funcional en la enfermedad de Alzheimer preclínica esporádica y asociada al síndrome de Down, Tau pathology in Down syndrome and Alzheimer's, Estudio de biomarcadores bioquímicos y de imagen de angiopatía amiloide cerebral en el continuum de la enfermedad de Alzheimer esporádica y asociada al síndrome de Down, Biological Correlates of Alzheimer in Down Syndrome., Bilingual Factors Associated with Cognitive Reserve and Linguistic Resilience in Hispanics with Primary Progressive Aphasia
OpenAlex ID: W7172003663