García-Alberca, José Maríade Rojas, ItziarSánchez-Mejías, ElisabethGarrido-Martín, DiegoGonzález-Palma, LauraJiménez, SebastiánMuñoz Castro, ClaraNavarro Garrido, VictoriaMir Rivera, PabloVitorica Ferrández, Francisco JavierGERALD consortium2025-09-052025-09-052024-03García-Alberca, J.M., de Rojas, I., Sánchez-Mejías, E., Garrido-Martín, D., González-Palma, L., Jiménez, S.,...,GERALD consortium, (2024). An Insertion Within SIRPbeta1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response. Journal of Alzheimer's Disease, 98 (2), 601-618.https://doi.org/10.3233/JAD-231150.1875-89081387-2877https://hdl.handle.net/11441/176766Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p=0.018) and a higher risk to develop AD (OR=1.678, p=0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p<0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p=0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.application/pdf32 p.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Alzheimer's diseaseCopy-number variantDAP12MicrogliaSIRPβ1TREM2TYROBPinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.3233/JAD-231150