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 SIRP{beta}1, a surface receptor expressed on the myeloid cells that triggers amyloid-{beta} and cell debris phagocytosis via TYROBP. We found that a common intragenic duplication alters the SIRP{beta}1 protein isoform landscape affecting both extracellular and transmembrane domains, which compromise their ability to bind oligomeric A{beta} and their affinity for TYROBP. Epidemiological studies show that patients with mild cognitive impairment that are homozygous for the SIRP{beta}1 duplication allele show an increased cerebrospinal fluid t-Tau/A{beta} 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 SIRP{beta}1 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.