White matter microstructure (WMM) potentially mediates the relation between APOE4 and memory performance. This study’s purpose was to understand whether p-tau effects this mediation model and whether education level differentially impacts the relations between these genetic and biological biomarkers’ influence on memory.

Participants included 161 older adults (M=74 years, 40.4% female, 92% White, 74 e4 non-carriers, 87 e4 carriers) with subjective and objective cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). A composite memory score created by ADNI was used as the outcome variable. Mean fractional anisotropy (FA) and radial diffusivity (RD) values of white matter tracts within regions of interest (i.e., fornix (FX), hippocampal cingulum (CGH)) were individually used as the measures of WMM. A moderated mediation was run to examine whether p-tau was a moderator of the mediation between APOE4, white matter microstructure, and memory. An exploratory dual moderated mediation analysis examined education as a moderator of the moderated mediation. Indirect effects were tested using bootstrapping procedures.

In the FA moderated mediation model, APOE4 was significantly related to FA of the fornix and memory performance. FA of the CGH and FX were also related to memory performance. With FA of the fornix as the mediator, the conditional indirect effect was not significant (95% CI[-.0009, .0070]). There was a trend suggesting at low (95% CI[-.2421, -.0140]) and average (95% CI[-.1658, -.0083]) levels of p-tau, FA of the fornix was a significant mediator but was non-significant at high levels of p-tau (95% CI [-.1322, .0341]). The RD moderated mediation model was non-significant. The FA and RD exploratory dual moderated mediation models were non-significant. However, the APOE4 x p-tau interaction with FA of the fornix as the mediator suggested a trend. At low levels of p-tau, increased education was related to a significant moderated mediation.

Results suggest that FA of the fornix is a significant mediator between the relation of APOE4 and memory, and this may be dependent upon p-tau levels. When p-tau burden load was high, the path by which APOE4 impacts memory performance was not through white matter microstructure degradation. Additionally, the potential buffering effects of education may be most robust at lower levels of p-tau burden.