Lower Hippocampal Volume Partly Mediates the Association Between rs6859 in the NECTIN2 Gene and Alzheimer’s Disease: New Findings from Causal Mediation Analysis of ADNI Data

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.