Differential Associations of APOEɛ2 and APOEɛ4 Genotypes with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease in Individuals Without Dementia

Abstract

Background: The APOE genotype has emerged as the major genetic factor for AD but differs among different alleles. Objective: To investigate the discrepant effects of APOE genotype on AD cerebrospinal fluid (CSF) biomarkers. Methods: A total of 989 non-demented ADNI participants were included. The associations of APOE ɛ2 and APOE ɛ4 with CSF biomarkers were investigated using linear regression models. Interaction and subgroup analyses were used to investigate the effects of sex and age on these associations. Furthermore, we used mediation analyses to assess whether Aβ mediated the associations between APOE genotypes and tau. Results: APOE ɛ2 carriers only showed higher Aβ levels (β [95% CI] = 0.07 [0.01, 0.13], p = 0.026). Conversely, APOE ɛ4 carriers exhibited lower Aβ concentration (β [95% CI] = –0.27 [–0.31, –0.24], p < 0.001), higher t-Tau (β [95% CI] = 0.25 [0.08, 0.18], p < 0.001) and higher p-Tau (β [95% CI] = 0.31 [0.25, 0.37], p < 0.001). Subgroup analysis showed that APOE ɛ2 was significantly positively associated with Aβ only in females (β [95% CI] = 0.12 [0.04, 0.21], p = 0.005) and older people (β [95% CI] = 0.06 [0.001, 0.12], p = 0.048). But the effects of APOE ɛ4 were independent of gender and age. Besides, the associations of APOE ɛ4 with t-Tau and p-Tau were both mediated by baseline Aβ. Conclusions: Our data suggested that APOE ɛ2 could promote Aβ clearance, while the process could be modified by sex and age. However, APOE ɛ4 might cause the accumulation of Aβ and tau pathology independent of sex and age.