APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure

Area of Science:

• Neuroscience
• Genetics
• Radiology

Background:

• Apolipoprotein E ɛ4 (APOE ɛ4) is the main genetic risk factor for sporadic Alzheimer's disease.
• Mechanisms linking APOE ɛ4 to neurodegeneration remain unclear.
• Cortical microstructure changes are early indicators of neurodegenerative processes.

Purpose of the Study:

• To investigate the impact of APOE ɛ4 on cortical microstructure in cognitively normal individuals.
• To examine interactions between APOE ɛ4, age, and education on brain structure.
• To elucidate how APOE ɛ4 influences age-related microstructural changes relevant to Alzheimer's disease.

Main Methods:

• Utilized the Neurite Orientation Dispersion Model on diffusion MRI data.
• Included 1954 participants from the PREVENT-Dementia and ALFA studies.
• Analyzed Orientation Dispersion Index (ODI) using FreeSurfer and Microstructure Diffusion Toolbox, with Permutation Analysis of Linear Models for statistical analysis.

Main Results:

• Identified significant APOE ɛ4 × age interactions in temporo-parietal and frontal lobes.
• APOE ɛ4 carriers exhibited steeper age-dependent declines in cortical ODI.
• Lower education levels exacerbated age-related ODI reductions in APOE ɛ4 carriers.

Conclusions:

• APOE ɛ4 accelerates age-related decreases in cortical ODI, especially in Alzheimer's-vulnerable brain regions.
• These microstructural changes suggest APOE ɛ4 may hasten dementia onset by accelerating neural aging.
• Findings highlight the role of APOE ɛ4 in modulating brain aging trajectories and dementia risk.