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ORIGINAL RESEARCH article

Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 16 - 2024 | doi: 10.3389/fnagi.2024.1388363
This article is part of the Research Topic Unraveling the Mysteries of Aging and the Brain: Advancements in Understanding Neurodegenerative Diseases & Dementia View all articles

The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau

Provisionally accepted

The final, formatted version of the article will be published soon.

    Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2.We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor).The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p<0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p<0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect.This study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Further research is needed to confirm the observed relationship and uncover the remaining mechanisms connecting variation in the NECTIN2 gene with AD.

    Keywords: Alzheimer's disease, NECTIN2 gene, rs6859, pTau-181, Causal mediation

    Received: 19 Feb 2024; Accepted: 18 Jul 2024.

    Copyright: © 2024 Lathika Rajendrakumar, Arbeev, Bagley, Yashin and Ukraintseva. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Aravind Lathika Rajendrakumar, Duke University, Durham, United States
    Svetlana Ukraintseva, Duke University, Durham, United States

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