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| Item Type: | Article |
|---|---|
| Title: | Alzheimer’s disease risk SNP rs11218343 is linked to functional expression of SORL1 in microglia |
| Creators Name: | Gorniak-Walas, Malgorzata, Telugu, Narasimha S., Rudolph, Ina-Maria, Diecke, Sebastian and Willnow, Thomas E. |
| 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. |
| Keywords: | Functional Validation of Risk Genotype, Genome-Wide Association, Human Induced Pluripotent Stem Cells, Microglia, Pro-Inflammatory Response, SORLA, Sporadic Alzheimer Disease |
| Source: | Alzheimer's & Dementia |
| ISSN: | 1552-5260 |
| Publisher: | Wiley |
| Volume: | 22 |
| Number: | 4 |
| Page Range: | e71390 |
| Date: | 2026 |
| Official Publication: | https://doi.org/10.1002/alz.71390 |
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