Key Points Question Is cognitive decline associated with amyloid-β or tau tangles accumulation? Findings In this cohort study that included 60 normal older adults with repeated positron emission tomography measures, the rate of tau accumulation in the inferior temporal neocortex was associated with the rate of cognitive decline. Amyloid accumulation was associated with subsequent tau accumulation, and this sequence of successive amyloid and tau changes in neocortex was found to mediate the association of initial amyloid with final cognition, measured 7 years later. Meaning Amyloid positron emission tomography is useful to detect early Alzheimer pathology; repeated tau positron emission tomography is useful to track disease progression.

Clinically normal individuals who are APOE ε4+ and have high Aβ showed the highest cognitive decline. These results suggest that Aβ and APOE ε4 are not redundant contributors of decline in aging but rather interact to promote decline during the short follow-up period examined in this study. Longer follow-up periods will be essential to fully elucidate the influence of Alzheimer disease risk factors on cognitive decline in aging.