# Associations Between Polygenic Risk for Alzheimer’s Disease and Grey Matter Volume Are Dependent on APOE, Pathological and Diagnostic Status

## TL;DR

This study explores how genetic risk for Alzheimer's disease relates to brain volume changes in different groups of people, including those with and without the disease.

## Contribution

The study reveals that genetic risk scores for Alzheimer's are linked to brain volume changes, but these associations depend on amyloid status, APOE, and diagnostic group.

## Key findings

- PRSs were negatively associated with grey matter volumes in specific brain regions like the hippocampus and amygdala.
- Associations were strongest in amyloid-negative non-atrophic participants and cognitively unimpaired or AD individuals.
- Findings did not survive correction for multiple testing using the false discovery rate.

## Abstract

Background/Objectives: Studies have shown that higher polygenic risk scores (PRSs) for Alzheimer’s disease (AD) are associated with smaller volumes in temporal brain regions typically affected by this disease. These effects have also been found in cognitively unimpaired (CU) older adults. This study aimed to investigate the relationship between PRSs and brain volumes in specific areas associated with early AD. Methods: 342 participants were selected from the Alzheimer’s Disease Neuroimaging Initiative and stratified into three groups: 114 amyloid-positive atrophic (A+N+), 114 amyloid-negative non-atrophic (A−N−), and 114 amyloid-positive non-atrophic (A+N−) people. Linear regressions were performed within each group to investigate associations between PRSs and regional grey matter volumes. Analyses were also repeated after stratifying groups by APOE status and clinical diagnosis. Two sensitivity analyses were run to investigate the impact of APOE and amyloid status and concordance across biomarkers. Multiplicity was controlled for using the Benjamini–Hochberg false discovery rate (FDR) approach. Results: Negative associations were observed between PRSs and volumes of the left amygdala and hippocampus in A+N+, right hippocampus in A+N−, and right posterior cingulate cortex in A−N− participants. Associations were found especially in A−N− participants, both ε4 allele carriers and non-carriers, and mostly confirmed in sensitivity analyses. Associations emerged only in CU and AD participants, but not in people with MCI. None of these findings survived correction for FDR. Conclusions: These findings highlight the potential of PRSs as novel biological indicators for a deeper characterisation of AD-related neural alterations.