APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-beta

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimers disease (AD). While APOE4 is strongly associated with amyloid-beta (A{beta}) accumulation, its relationship with tau accumulation is less understood. Studies evaluating the role of APOE4 on tau accumulation have shown conflicting results, particularly regarding the independence of these associations from A{beta} load. To clarify the relations between APOE4, A{beta} and tau, we examined three independent longitudinal cohorts (the Swedish BioFINDER-1, BioFINDER-2 and WRAP cohorts) in which participants had cross-sectional and longitudinal measures of tau tangles (tau-PET; temporal meta-ROI and entorhinal) or soluble p-tau (p-tau217), A{beta}-PET and APOE genotype. The study included a total of 1370 cognitively unimpaired (CU) and 449 mild cognitive impairment (MCI) subjects, followed longitudinally with tau-PET and p-tau217. APOE4 carriers accounted for 40.2-50% of the cohorts. Different linear regressions (cross-sectional) and linear mixed-effect models (longitudinal) with tau measures as outcomes were fitted to test the effect of APOE4 as independent predictor, as well as in combination with baseline A{beta} load or the interaction term between APOE4 and A{beta} load. All models included age, sex and cognitive status as covariates. We found no independent effects of the APOE4 carriership on insoluble tau aggregates in either cohort (BioFINDER-2 or WRAP), both on cross-sectional and longitudinal tau-PET levels in the temporal meta-ROI, when A{beta} was present in the model (p=0.531-0.949). A{beta} alone was the best predictor of insoluble tau accumulation, and there was no interaction between APOE4 and A{beta} on tau-PET. Similarly, no independent effects of the APOE4 carriership on baseline (p=0.683-0.708) and longitudinal (p=0.188-0.570) soluble p-tau217 were observed when A{beta} was included in the model in BioFINDER-1 and WRAP. No interaction between APOE4 and A{beta} on soluble p-tau217 was observed. Furthermore, mediation analysis revealed that A{beta} load fully mediated most associations between APOE4 and tau (46-112%, either cross-sectional or longitudinal tau-PET or soluble p-tau217). In the largest cohort (BioFINDER-2), looking at APOE4 groups based on the number of {varepsilon}4 alleles, we found an interaction between APOE4 homozygotes only and A{beta} on tau-PET levels at baseline and over time. In conclusion, although APOE4 is strongly associated with A{beta} aggregation, it seems to be minimally associated with longitudinal changes in soluble or insoluble p-tau levels at a given level of A{beta} pathology, confirming the primacy of A{beta} in driving tau pathology.