TY  - CONF
AU  - Zaragoza-Ballester, Pablo
AU  - Nuscher, Briggitte
AU  - Alcolea, Daniel
AU  - Fernández-León, Álex
AU  - Rodríguez-Baz, Íñigo
AU  - Bejanin, Alexandre
AU  - Vera, Elena
AU  - Vaqué-Alcázar, Lídia
AU  - Sala, Isabel
AU  - Gómez-Grande, Adolfo
AU  - Lleo, Alberto
AU  - Fortea, Juan
AU  - Camacho, Valle
AU  - Haass, Christian
AU  - Morenas-Rodriguez, Estrella
TI  - Association between soluble TREM2, APOE genotype, Alzheimer's copathology and disease evolution in dementia with Lewy bodies
JO  - Alzheimer's and dementia
VL  - 21
IS  - Suppl 1
SN  - 1552-5260
M1  - DZNE-2025-01486
SP  - e102529
PY  - 2025
AB  - APOEε4 is a genetic risk factor for both Alzheimer's Disease (AD) and dementia with Lewy bodies (DLB). TREM2-dependent microglial activation is considered protective in AD and has been proposed to interact with APOE in this context. Since DLB often exhibits Alzheimer's copathology, we investigate the interplay between TREM2 response, APOEε4 carriage and Alzheimer's co-pathology, and its influence on disease evolution in DLB.We measured cerebrospinal fluid (CSF) cleaved soluble TREM2 (cTREM2), as a marker of TREM2-dependent microglial response, core AD biomarkers and determine APOEε4 carriage in 76 DLB patients (prodromal DLB [prodDLB], n = 39; DLB-dementia, n = 37). Forty one patients additionally underwent [18F]Florbetapir-PET (FBP-PET). We quantified cTREM2 by an in-house MSD-based immunoassay; core AD biomarkers (Aβ42, t-tau, p-tau181), by ELISA; and FBP-PET uptake, by standard uptake value ratio (SUVr). We stratified patients according to the A/T classification. Clinical follow-up (>1 year) was available for 69 patients.APOEε4 carriers had lower cTREM2 levels compared to non-carriers in prodDLB (3.72±1.79vs.6.83±2.25ng/mL, p-value=0.0005, Figure 1). Furthermore, APOEε4 carriage itself was associated with lower cTREM2 levels in prodDLB (β(carriers)=-0.42, p-value=0.025) independently of AD core biomarkers. Conversely, APOEe4 carriage did not impact cTREM2 levels in DLB-dementia. cTREM2 levels across A-/+ and T-/+ DLB groups are represented in Figure 1. In prodDLB, higher cTREM2 levels were associated with higher Aβ42 (β=0.77, p-value=0.0002) and p-tau181 levels (β=0.612, p-value=0.002). In DLB-dementia, cTREM2 levels were associated only with p-tau181 (β=0.58, p-value=0.0001). Additionally, higher cTREM2 levels were associated with lower FBP-PET SUVr in prodDLB (β=-1.71, p-value=0.04). Notably, higher sTREM2 levels at baseline in prodDLB were related to a smaller subsequent longitudinal decrease in MMSE scores (β=1.11, p-value=0.01). No significant relationship was observed between baseline cTREM2 at a DLB-dementia stage and subsequent cognitive decline (β=-0.3, p-value=0.5).APOEε4 carriage attenuates the TREM2-dependent microglial response in prodromal DLB, as reflected by lower CSF cTREM2 levels. Elevated cTREM2 levels in the prodromal phase are associated with slower cognitive decline, suggesting a protective role of microglial activation during early disease stages. These findings suggest an early modulation of TREM2-driven microglial response by APOEε4 which influences DLB progression.
T2  - Alzheimer’s Association International Conference
CY  - 27 Jul 2025 - 31 Jul 2025, Toronto (Canada)
Y2  - 27 Jul 2025 - 31 Jul 2025
M2  - Toronto, Canada
KW  - Humans
KW  - Male
KW  - Female
KW  - Aged
KW  - Biomarkers: cerebrospinal fluid
KW  - Apolipoprotein E4: genetics
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: cerebrospinal fluid
KW  - Alzheimer Disease: pathology
KW  - Lewy Body Disease: genetics
KW  - Lewy Body Disease: cerebrospinal fluid
KW  - Lewy Body Disease: diagnostic imaging
KW  - Lewy Body Disease: pathology
KW  - Membrane Glycoproteins: cerebrospinal fluid
KW  - Receptors, Immunologic
KW  - Amyloid beta-Peptides: cerebrospinal fluid
KW  - Positron-Emission Tomography
KW  - tau Proteins: cerebrospinal fluid
KW  - Middle Aged
KW  - Aged, 80 and over
KW  - Biomarkers (NLM Chemicals)
KW  - TREM2 protein, human (NLM Chemicals)
KW  - Apolipoprotein E4 (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Receptors, Immunologic (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)1 ; PUB:(DE-HGF)16
C6  - pmid:41436355
C2  - pmc:PMC12727221
DO  - DOI:10.1002/alz70855_102529
UR  - https://pub.dzne.de/record/283079
ER  -