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 Alzheimer’s disease (AD). While APOE4 is strongly associated with amyloid-beta (Aβ) 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 Aβ load. To clarify the relations between APOE4, Aβ 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), Aβ-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 Aβ load or the interaction term between APOE4 and Aβ 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 Aβ was present in the model (p=0.531-0.949). Aβ alone was the best predictor of insoluble tau accumulation, and there was no interaction between APOE4 and Aβ 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 Aβ was included in the model in BioFINDER-1 and WRAP. No interaction between APOE4 and Aβ on soluble p-tau217 was observed. Furthermore, mediation analysis revealed that Aβ 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 ε4 alleles, we found an interaction between APOE4 homozygotes only and Aβ on tau-PET levels at baseline and over time.

In conclusion, although APOE4 is strongly associated with Aβ aggregation, it seems to be minimally associated with longitudinal changes in soluble or insoluble p-tau levels at a given level of Aβ pathology, confirming the primacy of Aβ in driving tau pathology.