Importance: Tau accumulation in Alzheimer disease (AD) is closely associated with cognitive impairment. Quantitating tau accumulation by positron emission tomography (PET) will be a useful outcome measure for future clinical trials in the AD spectrum. Objective: To investigate the association of β-amyloid (Aβ) on PET with subsequent tau accumulation on PET in persons who were cognitively unimpaired (CU) to gain insight into temporal associations between Aβ and tau accumulation and inform clinical trial design. Design, Setting, and Participants: This cohort study included individuals aged 65 to 85 years who were CU and had participated in the Mayo Clinic Study of Aging, with serial cognitive assessments, serial magnetic resonance imaging, 11C-Pittsburgh compound B (Aβ) PET scans, and 18F-flortaucipir PET scans, collected from May 2015 to March 2020. Persons were excluded if they lacked follow-up PET scans. A similarly evaluated CU group from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were also studied. These data were collected from September 2015 to March 2020. Exposures: Participants were stratified by index Aβ levels on PET into low Aβ (≤8 centiloid [CL]), subthreshold Aβ (9-21 CL), suprathreshold Aβ (22-67 CL), and high Aβ (≥68 CL). Main Outcomes and Measures: Changes over a mean of 2.7 (range, 1.1-4.1) years in flortaucipir PET in entorhinal, inferior temporal, and lateral parietal regions of interest and an AD meta-region of interest (ROI). Results: A total of 167 people were included (mean age, 74 [range, 65-85] years; 75 women [44.9%]); 101 individuals were excluded lacking follow-up, and 114 individuals from the ADNI were also studied (mean [SD] age, 74.14 [5.29] years; 64 women [56.1%]). In the Mayo Clinic Study of Aging, longitudinal flortaucipir accumulation rates in the high Aβ group were greater than the suprathreshold, subthreshold, and low Aβ groups in the entorhinal ROI (suprathreshold, 0.025 [95% CI, 0.013-0.037] standardized uptake value ratio [SUVR] units; subthreshold, 0.026 [95% CI, 0.014-0.037] SUVR units; low Aβ, 0.034 [95% CI, 0.02-0.049] SUVR units), inferior temporal ROI (suprathreshold, 0.025 [95% CI, 0.014-0.035] SUVR units; subthreshold, 0.027 [95% CI, 0.017-0.037] SUVR units; low Aβ, 0.035 [95% CI, 0.022-0.047] SUVR units), and the AD meta-ROI (suprathreshold, 0.023 [95% CI, 0.013-0.032] SUVR units; subthreshold, 0.025 [95% CI, 0.016-0.034] SUVR units; low Aβ, 0.032 [95% CI, 0.021-0.043] SUVR units) (all P <.001). Flortaucipir accumulation rates in the subthreshold and suprathreshold Aβ groups in temporal regions were nonsignificantly elevated compared with the low Aβ group. In the ADNI cohort, the variance was larger than in the Mayo Clinic Study of Aging but point estimates for annualized flortaucipir accumulation in the inferior temporal ROI were very similar. An estimated 216 participants who were CU per group with PET Aβ of 68 CL or more would be needed to detect a 25% annualized reduction in flortaucipir accumulation rate in the AD meta-ROI with 80% power. Conclusions and Relevance: Substantial flortaucipir accumulation in temporal regions is greatest in persons aged 65 to 85 years who were CU and had high initial Aβ PET levels, compared with those with lower Aβ levels. Recruiting persons who were CU and exhibiting Aβ of 68 CL or more on an index Aβ PET is a feasible strategy to recruit for clinical trials in which a change in tau PET signal is an outcome measure..