# 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

## TL;DR

This study suggests that lower hippocampal volume partially explains how a genetic variant in NECTIN2 increases Alzheimer’s disease risk.

## Contribution

The novel finding is that hippocampal volume mediates the genetic risk of AD associated with rs6859 in NECTIN2.

## Key findings

- Carrying the rs6859 risk allele is associated with reduced hippocampal volume in males.
- Hippocampal volume mediates up to nearly 50% of the genetic risk effect on AD.
- The mediation effect was observed in ADNI data but requires validation in other populations.

## Abstract

Alzheimer’s disease (AD) is a complex disorder influenced by many factors. The rs6859 polymorphism in the NECTIN2 gene has been consistently linked to AD risk. The NECTIN2 is involved in vulnerability to infections, which could contribute to neurodegeneration. We hypothesized that hippocampal volume (HV), a biomarker of neurodegeneration, may mediate the connection between the NECTIN2 polymorphism and AD.

The analysis was conducted using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear mixed models were used to evaluate the association between SNP rs6859 and normalized hippocampal volumes over time. Multivariable linear and logistic regression models were used to estimate the associations between SNP rs6859 and median hippocampal volumes, and between SNP rs6859 and median hippocampal volumes and AD, adjusting for potential confounders. Causal mediation analyses (CMA) were performed using previously fitted logistic and linear models to estimate the mediating role of hippocampal volumes in the association between rs6859 and AD.

We found that smaller HV significantly mediates the association between rs6859 in NECTIN2 and AD risk. Carrying the rs6859 risk allele (A) was associated with lower 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 linear mixed models. These associations were significant only in males. The mediated effects for the right and left HV were 42.75 and 49.76%, respectively.

Our results indicate that hippocampal atrophy may mediate the association between NECTIN2 polymorphism and AD risk, although the borderline significance of these associations warrants confirmation in other populations.