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. 2022 Jun 21;14(1):e12317.
doi: 10.1002/dad2.12317. eCollection 2022.

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

Jung-Min Pyun  1   2 , Young Ho Park  1 , Angela Hodges  3 , Jae-Won Jang  4 , Paula J Bice  5 , SangYun Kim  1 , Andrew J Saykin  5   6 , Kwangsik Nho  5   7 ; AddNeuroMed Consortium and the Alzheimer's Disease Neuroimaging Initiative
Affiliations

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

Jung-Min Pyun et al. Alzheimers Dement (Amst). .

Abstract

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.

Keywords: Alzheimer's disease pathology; IFITM3; amyloid; biomarkers; clinical progression; cognitive decline; neurodegeneration; single nucleotide polymorphisms; tau.

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Conflict of interest statement

The authors declares that there are no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Association of rs10751647 with longitudinal cognitive decline and disease progression from MCI to dementia. Association of rs10751647 with longitudinal cognitive decline and disease progression from MCI to dementia was analyzed using a linear mixed effects model and Cox proportional hazard model, respectively, adjusted for age, sex, and education. As the number of minor alleles of rs10751647 increases, rs10751647 was associated with less cognitive decline rates (P‐value of 6.63× 10–8 in ADNI [A] and 2.30× 10–3 in AddNeuroMed [B]) and decreased risk of disease progression from MCI to dementia (HR 0.79 in ADNI [C]). ADAS‐COG, Alzheimer's Disease Assessment Scale–Cognitive subscale; ADNI, Alzheimer's Disease Neuroimaging Initiative; HR, hazard ratio; MCI, mild cognitive impairment
FIGURE 2
FIGURE 2
Association of rs10751647 with brain amyloid deposition in amyloid PET and p‐tau levels in CSF in ADNI. Association of rs10751647 with amyloid and tau burden was analyzed using linear regression models adjusted for age, sex, and education. As the number of minor alleles of rs10751647 increases, rs10751647 was associated with less amyloid burden in amyloid PET (P‐value = 8.65× 10–4) (A) and less p‐tau levels in CSF (P‐value = 6.59× 10–3) (B). ADNI, Alzheimer's Disease Neuroimaging Initiative; CSF, cerebrospinal fluid; PET, positron emission tomography; p‐tau, phosphorylated tau; SUVR, standardized uptake value ratio
FIGURE 3
FIGURE 3
Whole brain association analysis of rs10751647 with amyloid deposition (amyloid PET) (A) and cortical thickness (MRI) (B) in ADNI. Whole‐brain voxel‐based imaging analysis (A) of amyloid deposition showed that more minor alleles of rs10751647 were significantly associated with reduced amyloid deposition in a widespread pattern, especially in the bilateral frontal, parietal, and temporal lobes. Statistical maps were thresholded using a false discovery rate for a multiple testing adjustment to a corrected significance level of 0.05. Whole‐brain surface‐based analysis (B) of cortical thickness across the brain surface showed that more minor alleles of rs10751647 were significantly associated with larger cortical thickness in the bilateral temporal lobes including the entorhinal cortex. Statistical maps were thresholded using a random field theory for a multiple testing adjustment to a corrected significance level of 0.05. ADNI, Alzheimer's Disease Neuroimaging Initiative; MRI, magnetic resonance imaging; PET, positron emission tomography
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