Association of Initial β-Amyloid Levels With Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment

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 beta-amyloid (A beta) on PET with subsequent tau accumulation on PET in persons who were cognitively unimpaired (CU) to gain insight into temporal associations between A beta 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, C-11-Pittsburgh compound B (A beta) PET scans, and F-18-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 A beta levels on PET into low A beta (<= 8 centiloid [CL]), subthreshold A beta (9-21 CL), suprathreshold A beta (22-67 CL), and high A beta (>= 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 A beta group were greater than the suprathreshold, subthreshold, and low A beta 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 A beta, 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 A beta, 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 A beta, 0.032 [95% CI, 0.021-0.043] SUVR units) (all P < .001). Flortaucipir accumulation rates in the subthreshold and suprathreshold A beta groups in temporal regions were nonsignificantly elevated compared with the low A beta 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 A beta 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 A beta PET levels, compared with those with lower A beta levels. Recruiting persons who were CU and exhibiting A beta of 68 CL or more on an index A beta PET is a feasible strategy to recruit for clinical trials in which a change in tau PET signal is an outcome measure. This cohort study investigates the association between beta-amyloid in positron emission tomography and subsequent tau accumulation in persons who were cognitively unimpaired, to gain insight into the temporal associations between beta-amyloid and tau accumulation. Question What is the association between beta-amyloid on positron emission tomography and subsequent flortaucipir accumulation in persons without cognitive impairment? Findings This cohort study of 167 persons aged 65 to 85 years from a population-based study that used C-11-Pittsburgh compound B A beta and F-18-flortaucipir tau positron emission tomography serial imaging found that individuals with the highest levels of beta-amyloid had much greater accumulation of flortaucipir on a subsequent positron emission tomography scan. Results were partially replicated in an Alzheimer's Disease Neuroimaging Initiative sample. Meaning Substantial flortaucipir accumulation occurs when beta-amyloid levels are 68 centiloid or more, while at lower beta-amyloid levels, there is little flortaucipir accumulation; clinical trials intending to use a tau positron emission tomography tracer as an outcome measure should recruit persons with high beta-amyloid levels.

Automated summary

This study investigated the association between beta-amyloid in positron emission tomography and subsequent tau accumulation in cognitively unimpaired individuals. The findings showed that individuals with higher levels of beta-amyloid had greater accumulation of tau on subsequent PET scans. This suggests that recruiting individuals with high beta-amyloid levels for clinical trials using tau PET as an outcome measure may be beneficial.