Immunity gene IFITM3 variant: Relation to cognition and Alzheimer's disease pathology

INTRODUCTION: We investigated single‐nucleotide polymorphisms (SNPs) in IFITM3, an innate immunity gene and modulator of amyloid beta in Alzheimer's disease (AD), for association with cognition and AD biomarkers. METHODS: We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. We performed gene‐based association analysis of SNPs in IFITM3 with cognitive performance and SNP‐based association analysis with cognitive decline and amyloid, tau, and neurodegeneration biomarkers for AD. RESULTS: Gene‐based association analysis showed that IFITM3 was significantly associated with cognitive performance. Particularly, rs10751647 in IFITM3 was associated with less cognitive decline, less amyloid and tau burden, and less brain atrophy in ADNI. The association of rs10751647 with cognitive decline and brain atrophy was replicated in AddNeuroMed. DISCUSSION: This suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immunity and infection in AD. HIGHLIGHTS: IFITM3 is significantly associated with cognitive performance. rs10751647 in IFITM3 is associated with cognitive decline rates with replication. rs10751647 is associated with amyloid beta load, cerebrospinal fluid phosphorylated tau levels, and brain atrophy. rs10751647 is associated with IFITM3 expression levels in blood and brain. rs10751647 in IFITM3 is related to less vulnerability to Alzheimer's disease pathogenesis.