Alzheimer's disease risk single nucleotide polymorphism rs11218343 is linked to functional expression of SORL1 in microglia

Abstract INTRODUCTION The rs11218343 is a non‐coding variant of genome‐wide significance for sporadic Alzheimer's disease (AD) with one of the most protective effects known to date. It localizes to SORL1 , encoding the AD risk factor Sortilin‐related receptor with A type repeats (SORLA). Still, the functional significance of rs11218343 for AD‐related processes remains unclear. METHODS We used induced pluripotent stem cell (iPSC) lines from donors, or genome‐engineered to carry major and minor rs11218343 alleles, to study the impact of rs11218343 on cellular activities. RESULTS We show that rs11218343 is uniquely linked to functional expression of SORLA in microglia, with increased expression in the protective allele correlating with reduced pro‐inflammatory responses. These anti‐inflammatory effects are seen in donor lines but not in single nucleotide polymorphism (SNP) ‐engineered isogenic lines, arguing that this polymorphism alone is insufficient but acting context‐dependent. DISCUSSION Our data infer genetically defined expression of SORL1 in microglia as a determinant of protection from pro‐inflammatory stimulation, a function likely encoded by a haplotype linked to rs11218343.