# Exploring the role of apolipoprotein ε4 in progressive myoclonic epilepsy type 1

## TL;DR

This study investigates how the APOE ε4 gene variant affects the severity and progression of a rare neurological disorder called progressive myoclonic epilepsy type 1.

## Contribution

The study explores the novel role of APOE ε4 as a potential modifier of phenotypic variability in EPM1 patients.

## Key findings

- APOE ε4 carriers showed better emotional well-being and quality of life despite more severe brain degeneration.
- Carriers exhibited greater preservation of hippocampal and amygdalar volumes but more cortical thinning and white matter degeneration.
- Findings suggest a complex relationship between APOE ε4 and neurodegeneration in EPM1.

## Abstract

Progressive myoclonic epilepsy type 1 (EPM1) is a neurodegenerative disease caused by biallelic variants in the cystatin B (CSTB) gene. Despite a progressive course, phenotype severity varies among patients, even within families. We studied the potential role of APOE ε4 in modifying phenotypic diversity in EPM1, given its established association with neurodegeneration, particularly in Alzheimer's disease.

APOE genotypes were determined for 65 genetically verified EPM1 patients homozygous for the CSTB expansion mutation. The Unified Myoclonus Rating Scale (UMRS), Quality of Life in Epilepsy Inventory‐31 questionnaire (QOLIE‐31), intellectual ability (WAIS‐R), clinical data, and quantitative neuroimaging data were compared between APOE ε4 carriers and noncarriers to assess potential correlations with EPM1 severity. Volumetric analysis was performed on MRI data, while diffusion tensor imaging (DTI) was analyzed using Tract‐Based Spatial Statistics (TBSS) and atlas‐based white matter (WM) tract region of interest (ROI) analysis.

The cohort included 20 ε4 carriers (16 ε3/ε4 and 4 ε4/ε4) and 45 ε4 noncarriers (36 ε3/ε3, 8 ε2/ε3, and 1 ε2/ε2). No significant differences were found in UMRS or disease duration. Carriers had better QOLIE‐31 scores in emotional well‐being (p = .047), energy/fatigue (p = .048), and medical effects (p = .024). In volumetric analysis, carriers exhibited greater preservation of bilateral hippocampal and amygdalar volumes but demonstrated more pronounced cortical thinning in the left lingual gyrus, right lateral occipital gyrus, and right posterior cingulate (p < .05). Carriers exhibited more widespread WM degeneration in DTI, characterized by reduced fractional anisotropy (FA) and increased mean diffusivity (MD).

Despite greater white matter degeneration and reduced cortical thickness, APOE ε4 carriers exhibited preserved deep brain volumes and better self‐reported well‐being. This study highlights the complex interplay between genetic factors and neurodegenerative processes. Our future research aims to provide more natural history data of EPM1 and correlate long‐term phenotypic data with additional geno‐phenotypic analyses.