Infections may contribute to neurodegeneration, including Alzheimer’s disease (AD). Polymorphism in the NECTIN2 gene has been linked to both AD and vulnerability to infections. We hypothesized that neurodegeneration may mediate the connection between this polymorphism and AD. To test this hypothesis, we conducted a causal mediation analysis (CMA) using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data. We found that smaller hippocampal volume (HV), a biomarker of neurodegeneration, significantly mediated the association between rs6859 in NECTIN2 and AD risk. For the right HV, the mediated effect was 42.75%, while for the left HV, it was 49.76%. In linear mixed models (LMM), carrying the rs6859 risk alleles (A) was associated with a reduction in right HV (β = -0.16, p = 0.03), left HV (β = -0.14, p = 0.04), and total HV (β = -0.15, p = 0.04). In this data, the rs6859 (A) was a risk factor for AD only in men. Our results suggest that hippocampal atrophy may substantially mediate the association between NECTIN2 polymorphism and AD risk.

The authors have declared no competing interest.

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG076019 and R01AG070487. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

ADNI study methods were approved by institutional review boards of all participating institutions. The authors have only conducted secondary analyses of de-identified participant data. The ADNI obtained written informed consent for all ADNI participants by following local legislation and ADNI requirements. ADNI studies follow Good Clinical Practices guidelines, the Declaration of Helsinki, and United States regulations (U.S. 21 CFR Part 50 and Part 56).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All analyses in this study were conducted using publicly available datasets, which are accessible online.

https://adni.loni.usc.edu