Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of β-amyloid (Aβ) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using 18F-flortaucipir (FTP) and 11C-Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aβ in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aβ+ indi...