The key hypothesis underlying the evolution of AD pathology in carriers of APOE4 and BCHE-K is that, in preclinical AD, activation of glia is net hypofunctional and results in the accumulation of amyloid pathology; in early AD, glial activation and tau and neurodegenerative pathology show focal increases in the MTL; and in later stage disease, glial activation accompanied by tau and neurodegenerative pathology spread across the neocortex. Here, APOE is linked to amyloidosis.