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TNFRSF1B Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer's Disease

Authors
  • Pillai, Jagan A.1, 2, 3
  • Bebek, Gurkan4, 5
  • Khrestian, Maria6, 7
  • Bena, James8
  • Bergmann, Cornelia C.7
  • Bush, William S.9
  • Leverenz, James B.1, 2, 3
  • Bekris, Lynn M.6, 7
  • 1 Department of Neurology, Cleveland Clinic, Cleveland, OH , (United States)
  • 2 Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH , (United States)
  • 3 Neurological Institute, Cleveland Clinic, Cleveland, OH , (United States)
  • 4 Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, OH , (United States)
  • 5 Department of Nutrition, Case Western Reserve University, Cleveland, OH , (United States)
  • 6 Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH , (United States)
  • 7 Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH , (United States)
  • 8 Department of Quantitative Health Science, Lerner Research Institute, Cleveland Clinic, Cleveland, OH , (United States)
  • 9 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH , (United States)
Type
Published Article
Journal
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Publication Date
Feb 25, 2021
Volume
13
Identifiers
DOI: 10.3389/fnagi.2021.638922
PMCID: PMC7947258
Source
PubMed Central
Keywords
License
Unknown

Abstract

Tumor necrosis factor receptor 2 (TNFR2) promotes neuronal survival downstream. This longitudinal study evaluated whether the TNFRSF1B gene encoding TNFR2 and levels of its soluble form (sTNFR2) affect Alzheimer disease (AD) biomarkers and clinical outcomes. Data analyzed included 188 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had mild cognitive impairment (MCI) and AD dementia. Further, a replication study was performed in 48 patients with MCI with positive AD biomarkers who were treated at a memory clinic. Cerebrospinal fluid (CSF) sTNFR2 levels along with two related TNFRSF1B gene single nucleotide polymorphisms (SNPs) rs976881 and rs1061622 were assessed. General linear models were used to evaluate the effect of CSF sTNFR2 levels and each SNP in relationship to CSF t-tau and p-tau, cognitive domains, MRI brain measures, and longitudinal cognitive changes after adjustments were made for covariates such as APOE ε 4 status. In the ADNI cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF t-tau and p-tau levels; hippocampal and whole brain volumes; and Digit Span Forwards subtest scores. In the replication cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF p-tau. A significant interaction between rs976881 and CSF sTNFR2 also impacts Clinical Dementia Rating Sum of Boxes scores over 12 months in the ADNI cohort. The interaction between TNFRSF1B variant rs976881 and CSF sTNFR2 levels was noted to modulate multiple AD-associated severity markers and cognitive domains. This interaction impacts resilience-related clinical outcomes in AD and lends support to sTNFR2 as a promising candidate for therapeutic targeting to improve clinical outcomes of interest.

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