Impact of Apolipoprotein E ε4 in Alzheimer’s Disease: Insights From a Meta-Analysis

Alzheimer’s disease (AD) is an escalating global health crisis, with an estimated 50 million individuals affected worldwide, and it has been predicted that this number will triple by 2050.¹ Characterized by progressive cognitive decline and memory loss, AD is an immense burden on affected individuals, their families, and healthcare systems.² Amid the multifaceted causes of AD, the apolipoprotein E (APOE) ε4 allele has emerged as a significant genetic risk factor.³ Recent meta-analyses have shed light on the profound impact of this allele on brain atrophy, offering new avenues for understanding and potentially mitigating this devastating disease.⁴

The APOE gene, located on chromosome 19, exists in three isoforms (ε2, ε3, and ε4), among which the ε4 variant is strongly associated with an increased risk of AD.⁵ Approximately 60% of AD patients carry the ε4 allele, which increases the risk of developing the disease by 2- to 3-fold if 1 allele is present and by up to 15-fold if 2 alleles are present.⁵ The presence of the APOE ε4 allele not only increases susceptibility but also accelerates disease progression and severity, highlighting the critical role of this allele in AD pathology.⁵

A recent coordinate-based meta-analysis of voxel-based morphometry studies yielded a comprehensive review of how the APOE ε4 allele influences brain structure. That study aggregated data from 12 neuroimaging studies, encompassing 1,135 individuals, to compare gray-matter atrophy between APOE ε4 carriers and noncarriers across different stages of cognitive decline.⁴ The analysis revealed significant atrophy in the hippocampus and parahippocampus of APOE ε4 carriers, particularly among those with AD and mild cognitive impairment. These regions are crucial for memory formation and cognitive function, and their atrophy is closely linked to the characteristic symptoms of AD.⁶ It is particularly interesting that healthy controls carrying the ε4 allele did not show significant atrophy, underscoring the specific impact of the allele in the presence of AD pathology.⁴

That previous study also used the Neurosynth platform to perform a meta-analytic coactivation analysis to reveal the functional networks associated with the observed atrophy patterns.⁴ One finding was that the parahippocampal gyrus cluster showed connectivity with the bilateral hippocampus and posterior cingulate cortex. This finding suggests that structural damage in these regions disrupts broader cognitive networks, contributing to the cognitive deficits seen in AD patients.⁴

The profound impact of the APOE ε4 allele on brain atrophy underscores the importance of early genetic screening and intervention. Identifying individuals with a genetic risk of AD would facilitate the implementation of targeted prevention strategies and personalized treatment plans. Early intervention might slow the progression of brain atrophy and mitigate cognitive decline.⁴

Despite the significant findings of that study, the authors acknowledged limitations such as the relatively small sample and the need for more direct comparisons between APOE ε4 carriers and noncarriers.⁴ Future research should aim to identify 1) the mechanistic pathways through which the APOE ε4 allele influences AD pathology and 2) the interplay between genetic and environmental factors.

The meta-analysis described here has provided critical insights into the role of the APOE ε4 allele in AD. By elucidating the patterns of brain atrophy associated with this genetic variant, the study has enhanced our understanding of AD to open new avenues for targeted interventions. As the fight against AD continues, integrating genetic screening with advanced neuroimaging techniques will be crucial to developing strategies that are effective in combating this debilitating condition.

In summary, the APOE ε4 allele significantly influences brain atrophy in AD, particularly in regions crucial for memory formation and cognitive function. Recognizing and addressing this genetic risk through early detection and personalized treatment plans holds promise for improving outcomes and enhancing the quality of life among those at risk of AD.

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.