APOE and tau in AD: K ey findings from human studies. A series of studies in humans have demonstrated that APOE ε4 is linked to exacerbated tau pathology. In PET studies, APOE ε4 has been linked to a more severe and Braak-like medial temporal accumulation of tau, whereas non-APOE ε4 individuals tend to present a more neocortical and mild tau burden. In the CSF, studies have shown that the levels of all tau markers (T-tau, p-tau, and tau aggregates) tend to increase in APOE ε4 individuals, an effect that appears to be modulated by sex and amyloid pathology (except for MTBR tau). Within the CSF, the tau biomarker levels do not appear to differ significantly between APOE ε2 and APOE ε3 individuals, despite the protective role of APOE ε2. RNA-seq studies have found that APOE ε4 appears to upregulate a series of genes, including genes associated with phagocytosis, cell death, and proinflammatory genes, whereas it downregulates neurotransmission and synaptic pathway genes.