MRI phenotype mediates the association between APOE4 and AD: A cross-sectional study

Background: Alzheimers disease (AD) is a prominent factor in mortality among older people. The precise biological mechanisms linking APOE4 and cognitive impairment in AD are still unclear, despite significant research efforts. Thus, our study aimed to explore the potential mediating role of MRI phenotypes in the relationship between APOE4 and cognitive impairment in AD. Methods: The white mass volume of MRI phenotypes was measured in 1721 older adults based on the ADNI. Linear regression was employed to explore the association of cognitive impairment and MRI phenotype with the APOE4 allele, respectively. Furthermore, the researchers performed mediation analyses to explore the potential mediating effect of the MRI phenotype on the relationship between the APOE4 allele and cognitive ability indicated by the MMSE score. The researchers also stratified the results by gender and by age to ensure comprehensiveness. Results: The research indicated that both the mean causal mediating effect (ACME) and the mean direct effect (ADE) of LH, RH, LA, and RA in relation to the APOE4 and MMSE score associations were negative. Besides, the white matter volume of the MRI phenotype mediated the relationship between APOE4 and MMSE scores, with mediation proportions of 47.5%, 43.7%, 33.1%, and 28.3%, respectively. Notably, the proportion mediated was higher in the hippocampus than in the amygdala, and it was also higher in the left hemisphere compared to the right hemisphere. All of these findings were statistically significant (p-value < 0.05). Additionally, when stratified by age, the older half of the participants exhibited higher ACME levels compared to the younger half, and when stratified by gender, females demonstrated higher ACME levels than males. Conclusions: The mediation analysis showed a good fit with previous studies. The model presents a promising target for further future studies on clinical diagnosis and potential therapeutic targets related to APOE4.