Immunity gene IFITM3 variant: relation to cognition and Alzheimer pathology

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Abstract Background IFITM3, an innate immune response protein and inhibitor of viral infection, was reported to modulate amyloid‐β production in Alzheimer’s disease (AD). We aimed to identify single‐nucleotide polymorphisms (SNPs) in IFITM3 associated with cognition and AD biomarkers. Method We used genetic, longitudinal cognition and AD biomarker data from Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 1,565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. First, we performed gene‐based association analysis of SNPs in IFITM3 with cognitive performance. Second, we performed SNP‐based association analysis in IFITM3 with cognitive decline and AD biomarkers from amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI). Result Gene‐based association analysis showed that IFITM3 was significantly associated with cognitive performance (permutation‐corrected p = 1.25×10−3). Particularly, among two SNPs (rs10751647, rs2091850) in IFITM3 significantly associated with cognitive performance, rs10751647 was associated with cognitive decline in ADNI, which was replicated in AddNeuroMed. In addition, rs10751647 was significantly associated with amyloid‐β deposition measured by amyloid PET scan, CSF phosphorylated tau levels, and entorhinal cortical thickness measured by MRI scan in ADNI. The association of rs10751647 with entorhinal cortical thickness was replicated in AddNeuroMed. Participants with minor alleles (C) of rs10751647 have less cognitive decline, less amyloid and tau burden, and less brain atrophy. eQTL analysis showed that rs10751647 is associated with IFITM3 expression levels in blood and brain. Conclusion This suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immune activity and infection in AD.

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