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

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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..

Original languageEnglish
Pages (from-to)217-228
Number of pages12
JournalJAMA Neurology
Issue number2
StatePublished - Feb 2021

Bibliographical note

Funding Information:
Funding/Support: This work was supported by

Funding Information:
Dr Vemuri receives research grants from the National Institute on Aging (NIA). Dr Mielke receives research support from the NIH (grants R01 AG49704, U54 AG44170, U01 AG06786, and RF1 AG55151), Department of Defense (grant W81XWH-15-1), and unrestricted research grants from Biogen, as well as other support from the Brain Protection Company outside the submitted work. Dr Machulda receives research support from the NIA and the National Institute on Deafness and Other Communication Disorders. Dr Lowe serves on scientific advisory boards for Bayer Schering Pharma, Philips Molecular lmaging, Life Molecular lmaging, AVID Radiopharmaceuticals, and GE Healthcare; receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, the NIA, and the National Cancer Institute; and receives personal fees from Eisai Inc, Avid Radiopharmaceuticals, and Piramal Imaging. Dr Kantarci receives research grants from the NIA and AVID Radiopharmaceuticals outside the submitted work. Dr Graff-Radford receives research grants from the NIA. Dr Boeve has served as an investigator for clinical trials sponsored by Biogen and Alector; receives publishing royalties from Behavioral Neurology of Dementia (Cambridge Medicine, 2009 and 2016); serves on the scientific advisory board of the Tau Consortium; receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation; and reports grants from the NIH during the conduct of the study and Biogen, Alector, and EIP Pharma outside the submitted work. Dr Therneau receives research grants from the NIH. Dr Petersen is a consultant for Biogen Inc, Hoffman–La Roche Inc, Merck Inc, Genentech Inc, and Eisai Inc; has given educational lectures for GE Healthcare; receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003) and UpToDate; and receives research support from the NIA. Dr Schwarz reported grants from the NIH outside the submitted work. Dr Jones reported grants from the NIH and the Minnesota Partnership for Biotechnology and Medical Genomics outside the submitted work. No other disclosures were reported.

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© 2021 American Medical Association. All rights reserved.

ASJC Scopus subject areas

  • Clinical Neurology


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