# Synergistic effect of APOE4 genotype and ELOVL2 methylation on cognitive slowing and verbal memory decline in non‐demented adults during aging

## TL;DR

This study shows how aging, APOE4 gene, and ELOVL2 methylation together affect brain function and memory decline in non-demented adults.

## Contribution

The study reveals a synergistic effect of APOE4 genotype and ELOVL2 methylation on cognitive and memory decline during aging.

## Key findings

- ELOVL2 methylation is linked to prolonged ERP P3 latency, especially in APOE4 carriers.
- APOE4 carriers show greater verbal memory decline with age compared to non-carriers.
- ELOVL2 methylation correlates with verbal memory decline only in APOE4 carriers.

## Abstract

Aging plays a crucial role in exacerbating the negative impact of the APOE4 genotype on brain function, heightening the risk of Alzheimer disease (AD). Methylation of the ELOVL2 promoter is a robust epigenetic biomarkers of age. ELOVL2 is involved in the production of long‐chain polyunsaturated fatty acids, which regulate synaptic plasticity and white matter integrity. P3 component of event‐related potentials (ERPs) elicited by the odd‐ball paradigm is a reliable marker of cognitive processing. This study investigated the associations between APOE genotype, ELOVL2 methylation and characteristics of the ERP P3 component and verbal memory in non‐demented adults during aging

We examined 75 non‐demented volunteers, age range 20‐84 years, 44 APOE4‐ and 31 APOE4+. Methylation of ELOVL2 promoter was measured in the blood. Auditory ERPs were recorded using the odd‐ball paradigm, and memory was assessed using the Luria verbal memory test. Informed written consent was obtained from all participants. All subjects underwent a neurological examination.

P3 latency was positively correlated with ELOVL2 methylation, and the correlation remained significant when age was statistically controlled, implying that epigenetic mechanisms might contribute to the prolongation of ERP latency. The correlation between ELOVL2 methylation and P3 latency was higher in APOE4 carriers than in noncarriers. The decrease of verbal memory during aging was more pronounced in APOE4 carriers than in non‐carriers. The partial correlation analysis controlling for age revealed a significant correlation between ELOVL2 methylation and verbal memory in APOE4+ carriers only. Moreover, ERP P3 latency was inversely correlated with verbal memory scores, and this correlation was stronger in APOE4+ carriers.

Impaired lipid metabolism linked to synaptic dysfunction and deterioration of white matter integrity, driven by age‐dependent ELOVL2 methylation, may accelerate the impact of the APOE4 genotype on neurophysiological slowing during aging. These changes may contribute to verbal memory decline in APOE4+ carriers and increase the risk of AD.

Funding: This study was supported by Russian Science Foundation (Project 19‐75‐30039 to TA genotyping; Project 22‐15‐00448 to NP, VF, EK ERP analysis and MP for genotyping) and by Ministry of Science and Higher Education of the Russian Federation (Agreement 075‐10‐2021‐093 project GEN‐RND‐2017).