Exploring the APOE ɛ4 Allele’s Pathways to Alzheimer’s: The Mediating Role of pTau-181

Background: Late-onset Alzheimer's Disease (LOAD) is a common form of dementia among older adults.The strongest genetic risk factor for LOAD is the APOE 4 gene.APOE 4 is associated with elevated biomarkers of LOAD, such as phosphorylated tau-181 (pTau-181).However, it is unknown how much of pTau-181's effect on the brain is facilitated by APOE 4.Our study aims to address this gap by estimating the indirect effect of APOE 4 on cognitive decline. Methods:We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset collected from 2004-2016 to explore the mediating effect of APOE 4 on pTau-181.All analyses were conducted in R. We evaluated the covariate associations for pTau-181 and AD with the covariates using adjusted linear and logistic regression models, respectively.We then assessed the mediation effects by combining these models and decomposing their effects into direct and indirect effects using the mediation package.We also stratified the mediation effects by sex and calculated the population attributable fraction (PAF). Results:The analyzed data comprises 1249 participants with a mean age of 74.3 years, and the majority were White (93.7%).Of all participants, 46.3% carried APOE 4.On average, 40.2% (95% CI: 23.6-69.8) of the APOE 4 effect was mediated through pTau-181.Indirect and proportion of mediated effects were higher among females (p < 0.01).The mediated PAF in the complete data was 19.9% (p < 0.01), and higher among females, 27.2% (p < 0.01), than males, 14.6% (p < 0.01). Conclusion:We found a substantial mediation effect on AD by APOE 4 through pTau-181.Therefore, it will be essential to understand the specific impact of APOE 4 on biomarkers to understand how it influences AD pathology.