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Alzheimer’s disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in <i>Saccharomyces cerevisiae</i>, using a library of 5154 gene knock-out strains expressing Aβ_1–42. We identified 81 mammalian orthologue genes that enhance Aβ_1–42 toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by Aβ oligomers (oAβ). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that <i>SURF4</i> silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, <i>SURF4</i> silencing produced a significant reduction in cell death when cells were challenged with oAβ_1–42, whereas <i>SURF4</i> overexpression induced Aβ_1–42 cytotoxicity. In summary, we identified new enhancer and protective activities for Aβ toxicity and showed that SURF4 contributes to oAβ_1–42 neurotoxicity by decreasing SOCE activity.