# The Effect of APOE ε4 Allele on Dynamic Local Spontaneous Brain Activity and Functional Integration in Alzheimer's Disease

## TL;DR

This study explores how the APOE ε4 gene affects brain activity and cognitive functions in Alzheimer's disease patients.

## Contribution

The study identifies how APOE ε4 influences dynamic brain activity and its link to cognitive decline and plasma biomarkers in Alzheimer's disease.

## Key findings

- APOE ε4 carriers showed unique correlations between brain activity in specific regions and cognitive scores.
- Voxel-wise concordance in the right caudate nucleus mediated the relationship between plasma Aβ42 and language function.
- A combined model using brain metrics and biomarkers effectively distinguished Alzheimer's patients from controls.

## Abstract

The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for sporadic Alzheimer's disease (AD), yet its mechanisms in AD pathology and cognitive decline remain unclear. Using a sliding‐time window approach to directly quantify the instantaneous fluctuations of various local metrics based on continuous time series and calculate voxel‐wise concordance of these metrics, we explored the impact of APOE ε4 on dynamic local brain activity and functional integration in AD, and its interrelations with plasma biomarkers and cognition. Results showed that APOE ε4 widely affected dALFF, dReHo, dGSCorr, and voxel‐wise concordance. For AD patients, APOE ε4 carriers uniquely exhibited correlations between dALFF in the right angular gyrus/supramarginal gyrus and MoCA scores and orientation function, and between voxel‐wise concordance in the right caudate nucleus (CAU) and general cognition, attention, language function, orientation function, plasma Aβ42. Critically, APOE ε4‐related altered voxel‐wise concordance in the right CAU mediated the relationship between plasma Aβ and language cognition in AD. Moreover, the combined model incorporating dynamic metrics, plasma AD biomarkers, and demographic data effectively distinguished AD from NC (AUC = 0.94, sensitivity = 87.69%, specificity = 86.84%). In conclusion, the APOE ε4 allele might play a pivotal role in modulating brain dynamic functional activities in AD, which may contribute to the association between Aβ pathology and cognitive decline. Our findings may provide imaging markers and targets for the diagnosis and treatment of AD.

The voxel‐wise concordance in the right CAU partially mediated the relationship between the plasma Aβ42 and language function in APOE ε4 carriers with AD.