To date, studies investigating the mechanism by which Ε4 and sex increase disease risk have primarily focused on the important associations of Ε4 with the neuropathological hallmarks of AD – i.e. the increased amyloid load seen in Ε4 carriers [9, 10] and the APOE-dependence of tau propagation [11, 12]. This evidence concerns the gene APOE and Alzheimer disease.