An intragenic duplication within SIRPβ1 shows a dual effect over Alzheimer’s disease cognitive decline altering the microglial response

Microglia play an important role in the maintenance of brain homeostasis, and microglial dysfunction plays a causative role in Alzheimer disease pathogenesis. Here we focus on the signal regulatory protein SIRPβ1, a surface receptor expressed on the myeloid cells that triggers amyloid-β and cell debris phagocytosis via TYROBP. We found that a common intragenic duplication alters the SIRPβ1 protein isoform landscape affecting both extracellular and transmembrane domains, which compromise their ability to bind oligomeric Aβ and their affinity for TYROBP. Epidemiological studies show that patients with mild cognitive impairment that are homozygous for the SIRPβ1 duplication allele show an increased cerebrospinal fluid t-Tau/Aβ ratio (p-value=0.018) and a higher risk to develop AD (OR=1.678, p-value=0.018). Magnetic resonance imaging at diagnosis showed that AD patients with the duplication allele exhibited a worse initial response to the disease. At the moment of diagnosis all patients showed equivalent Mini-Mental State Examination scores. However AD patients with the duplication allele had less hippocampal degeneration (Beta= -0.62, p-value < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline after correcting by baseline (p-value = 0.013). Transcriptional analysis of the patients’ hippocampus also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Given the recent pharmacological approaches focused on the TREM2-TYROBP axis, we consider that the presence of this structural variant might be considered as a potential modulator of this causative pathway. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project did not receive any specific public nor private funding. It has been possible only thanks to the goodwill and the collaborative effort of the researchers and institutions signing this paper. RG acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme, Generalitat de Catalunya. RG is principal investigator from grant PGC2018 094017 BI00 from AEI, FEDER, EU. AG is principal investigator of Instituto de Salud Carlos III of Spain grants PI18 01557 and P21 00915 co-financed by the FEDER funds from European Union. JV is principal investigator of ISCIII grants PI18 01556 and PI21 00914 cofinanced by FEDER funds from European Union, and Junta Andalucia grant US 1262734 cofinanced by Programa Operativo FEDER 2014 2020. JJT is principal investigator of PID2019 103921GB I00 from the Spanish Ministerio de Ciencia e Innovacion. JLR is principal investigator of UMA20 FEDERJA 133 from the program FEDER Andalucia 2014 2020, EU. JLR also acknowledges the Centro de Supercomputacion y Bioinformatica (Picasso-server) for computing support I. de Rojas is supported by national grant from the Instituto de Salud Carlos III FI20 00215. CM C was supported by FPU fellowship from the Spanish Ministry of Science, Innovation, and Universities. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria La Caixa, Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects, grant numbers 115975 and 115985, respectively. M.B. and A.R. are also supported by national grants PI13 02434, PI16 01861, PI17 01474, PI19 01240 and PI19 01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III) Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER Una manera de hacer Europa). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: GR@ACE series was recruted upon de approval from the Ethics Committee H., Clinic I Provincial, Barcelona, Spain. GERALD series was recruited upon de approval from the cometee from the Centro Provincial de Malaga, Malaga, Spain. Human hippocampal autopsy specimens were obtained from the Neurological Tissue Bank of IDIBAPS-Hospital Clinic (Barcelona, Spain). The utilization of post-mortem human samples was approved by the biobank ethic committee (Barcelona, Spain). Control samples were obtained from the National DNA Bank Carlos III University of Salamanca, (Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain) with the corresponding approval of the Ethical and Scientific Committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors upon the approval of the ethic's review board.