Alzheimer’s disease is the most common cause of dementia worldwide, and longitudinal studies are crucial to find the factors affecting disease development. Here, we describe a novel initiative from southern Spain designed to contribute in the identification of the genetic component of the cognitive decline of Alzheimer’s disease patients. The germline variant rs9320913 is a C>A substitution mapping within a gene desert. Although it has been previously associated to a higher educational achievement and increased fluid intelligence, its role on Alzheimer’s disease risk and progression remains elusive. A total of 407 subjects were included in the study, comprising 153 Alzheimer disease patients and 254 healthy controls. We have explored the rs9320913 contribution to both Alzheimer disease risk and progression according to the Mini-Mental State Exams. We found that rs9320913 maps within a central nervous system lincRNA AL589740.1. eQTL results show that rs9320913 correlated with the brain-frontal cortex ( beta = − 0.15 , p value = 0.057) and brain-spinal cord (beta of -0.23, p value = 0.037). We did not find rs9320913 to be associated to AD risk, although AA patients seemed to exhibit a less pronounced Mini-Mental State Exam score decline.

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 amyloidβ 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 tTau 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.