Neurodegenerative disorders, such as Alzheimer’s disease (AD), are the object of intense investigation due to their prevalence worldwide and the lack of an effective treatment to mitigate cognitive deterioration. This is because we still do not fully understand what triggers sporadic AD although several risk factors that predisposed disease development have been identified. Among them, genetic variants of the Apolipoprotein E (ApoE) or gene mutations in ADAM10 or TREM2 proteins have attracted particular attention, either for their prevalence and/or their relationship to glial cell function. In this context, innovative studies from our laboratory have demonstrated the multifunctional participation of the glial derived Secreted Frizzled Related Protein 1 (SFRP1) in AD pathology. By inhibiting ADAM10, SFRP1 blocks the non-amyloidogenic pathway, thus favoring the accumulation of amyloid-ß peptide levels. Furthermore, astrocyte-derived SFRP1 fosters microglia response to chronic neuroinflammation promoting the activation of components of the hypoxia inducible factor-1α (HIF-1α) pathway. Taken together, these observations support the possibility that SFRP1 may associate with glial-derived factors that predispose to AD, perhaps aggravating AD pathology. RNAseq studies have demonstrated an expression dependence between ApoE and SFRP1, as well as alterations in the expression of genes acting downstream of HIF-1α in Sfrp1-/- mice, which we are confirming in glial cell cultures. Biochemical studies indicate that ApoE and SFRP1 do not physically interact but proximity ligation assays in astrocyte cell cultures suggest that both proteins are closely located. Ongoing studies are addressing the physiological significance of these results in the context of AD associated neuroinflammation.