Association of Initial β-Amyloid Levels With Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment
Open accessAbstract
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.
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Amyloid plaque burden must be lowered to approximately 20 centiloids for a significant clinical benefit to become apparent.
“amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [26]
Amyloid-beta pathology drives tau pathology in Alzheimer disease.
“we propose that Aβ pathology drives tau pathology”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [26]
In cognitively normal participants, only those with amyloid burden above 68 centiloids showed a significant annualized increase in tau PET SUVR.
“They demonstrated that only in the >68 CL group was there a significant increase in annualized change in tau PET standard uptake value ratio (SUVR).”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [26]
The annualized rate of tau PET SUVR increase reached a plateau at about 100 centiloids, except in the entorhinal cortex where it continued to rise.
“the annualized rate in tau PET SUVR increase reached a plateau at approximately 100 CL, with the exception of the entorhinal cortex, where the rate continued to increase over the study period”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [26]
In cognitively normal subjects aged 65-85, there is no increase in annualized tau PET signal below 21 centiloids, but above 68 centiloids tau PET signal significantly increases.
“Knopman et al. 26 have shown that there is no increase in annualized tau PET signal in cognitively normal subjects aged 65-85 years below a threshold of 21 CL, but that above 68 CL, tau PET signal significantly increases.”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [26]
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Amyloid‐β in Alzheimer's disease: Structure, toxicity, distribution, treatment, and prospects
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“109 Regarding prognosis, individuals with baseline cerebrospinal fluid (CSF) A β 42 levels in the lower half of the reference range were more likely to develop subsequent A β positivity.”
BackgroundAmyloid PET detects the deposition of brain Aβ earlier than CSF fluid biomarkers
Lowe, V. J., Mester, C. T., Lundt, E. S., Lee, J., Ghatamaneni, S., Algeciras‐Schimnich, A., Campbell, M. R., Graff‐Radford, J., Nguyen, A. T., Min, H.-K. P., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14317 · Cited by 19 · see citing works
Self-citationSpatial extent as a sensitive amyloid‐PET metric in preclinical Alzheimer's disease
Farrell, M. E., Thibault, E. G., Becker, J. A., Price, J. C., Healy, B. C., Hanseeuw, B. J., Buckley, R. F., Jacobs, H. I. L., Schultz, A. P., Chen, C. D., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14036 · Cited by 13 · see citing works
“45,46 PriorPETstudiessupportthe idea that a threshold level of A β must be reached before this triggering event occurs, 40,47 with emerging support for a threshold around 50 CL. 40,48,49 Our findings also support further research to enable EXT metrics to be used in clinical trial design.”
ResultJiang, C., Wang, Q., Xie, S., Chen, Z., Fu, L., Peng, Q., Liang, Y., Guo, H., Guo, T., & Initiative, A. D. N. (2022) · Brain Communications · doi:10.1093/braincomms/fcac084 · Cited by 14 · see citing works
Self-citationTau accumulation in autosomal dominant Alzheimer’s disease: a longitudinal [18F]flortaucipir study
O’Connor, A., Cash, D. M., Poole, T., Markiewicz, P. J., Fraser, M. R., Malone, I. B., Jiao, J., Weston, P. S. J., Flores, S. E., Hornbeck, R. C., et al. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01234-5 · Cited by 14 · see citing works
“As in our study, the absence of group differences may be partly due to an over-representation of individuals far from symptom onset, as significantly higher longitudinal FTP accumulation rates, compared to amyloid-negative cases, are not found in all amyloidpositive individuals but only among a subset with very high l…”
BackgroundResultTau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer’s disease
Ramanan, V. K., Heckman, M. G., Lesnick, T. G., Przybelski, S. A., Cahn, E. J., Kosel, M., Murray, M. E., Mielke, M. M., Botha, H., Graff‐Radford, J., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02419-2 · Cited by 11 · see citing works
Self-citationBourgeat, P., Krishnadas, N., Doré, V., Mulligan, R. S., Tyrrell, R., Bozinovski, S., Huang, K., Fripp, J., Villemagne, V. L., & Rowe, C. C. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.17 · Cited by 10 · see citing works
“Recent work from Knopman and colleagues (2) showed that the rate of tau increase detected using 18F-FTP was much higher in subjects with high Aβ load, and this could explain differences between studies if their respective distribution of Aβ load at baseline is significantly different.”
BackgroundUpdate on neuroimaging in Alzheimer's disease
Sintini, I., & Whitwell, J. L. (2021) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000947 · Cited by 10 · see citing works
Cherdak, M. A. (2023) · Problems of Geroscience · doi:10.37586/2949-4745-2-2023-71-79 · Cited by 9 · see citing works
Giuffrè, G. M., Quaranta, D., Citro, S., Morganti, T. G., Martellacci, N., Vita, M. G., Rossini, P. M., Calabresi, P., & Marra, C. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240150 · Cited by 8 · see citing works
Latent change‐on‐change between amyloid accumulation and cognitive decline
Klinger, H. M., Healy, B. C., Hanseeuw, B. J., Jones, R. N., Boyle, R. T., Townsend, D. L., Properzi, M. J., Coughlan, G., Seto, M., Birkenbihl, C. J., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14326 · Cited by 6 · see citing works
Elasfar, S., Hameed, H., Boeve, B. F., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14351 · Cited by 8 · see citing works
Self-citationDefining patient‐centered amyloid PET thresholds for the onset of tauopathy in Alzheimer's disease
Zhu, Z., Steward, A., Dehsarvi, A., Roemer, S. N., Dewenter, A., Biel, D., Hirsch, F., Frontzkowski, L. K., Pescoller, J., Klonowski, M., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71064 · Cited by 8 · see citing works
“24 29 This is supported by results from the Clarity AD phase 3 trial of lecanemab, showing attenuated clinical efficacy of anti-A β treatment in younger versus older patients and in women versus men.”
InfluentialSelf-citationPark, S., Kim, K., Yoon, S., Kim, S., Ahn, J., Lim, K. Y., Jang, H., Na, D. L., Kim, H. J., Moon, S. H., et al. (2025) · Dementia and Neurocognitive Disorders · doi:10.12779/dnd.2025.24.2.135 · Cited by 7 · see citing works
“16,18,19 20-23 To address the limitations of a purely global approach, our group developed regional Centiloid scales (rdcCL) that harmonize A β uptake across various PET ligands using computed tomography (CT) images acquired during PET-CT scans for anatomical reference.”
Acute Regression in Down Syndrome
Handen, B. L., Clare, I. C. H., Laymon, C. M., Petersen, M. E., Zaman, S. H., O’Bryant, S. E., Minhas, D. S., Tudorascu, D., Brown, S. S. G., & Christian, B. T. (2021) · Brain Sciences · doi:10.3390/brainsci11081109 · Cited by 7 · see citing works
Kordi, R., Andrews, T. J., & Hicar, M. D. (2025) · Virology · doi:10.1016/j.virol.2025.110523 · Cited by 6 · see citing works
Cody, K. A., Sokolowski, A., Johns, E., Guerra, L. M., Winer, J. R., Young, C. B., Younes, K., Dumitrescu, L. C., Archer, D. B., Durant, A., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71017 · Cited by 3 · see citing works
The GPCR Connection: Linking Alzheimer's Disease and Glioblastoma
Caniceiro, A. B., Agostinho, S. P., Piochi, L. F., Rosário‐Ferreira, N., & Moreira, I. S. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.71131 · Cited by 4 · see citing works
Wang, X., Ye, T., Zhou, W., Zhang, J., & Initiative, A. D. N. (2025) · Neurology · doi:10.1212/wnl.0000000000214041 · Cited by 2 · see citing works
Self-citationKhandayataray, P., & Murthy, M. K. (2025) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-025-00688-z · Cited by 2 · see citing works
Precision pathways: optimising amyloid PET for sustainable Alzheimer’s disease care
Morbelli, S. D., Bozzali, M., Cagnin, A., Cecchin, D., Chiti, A., & Filippi, M. (2026) · Journal of Neurology · doi:10.1007/s00415-026-13874-2 · Cited by 2 · see citing works
“On the other hand, existing evidence suggests that an amyloid load exceeding the 60–70 Centiloid threshold may predict significant tau deposition, as assessed by [18F] flortaucipir PET [28, 29].”
Wybitul, M., Buchmann, A., Langer, N., Höck, C., Treyer, V., & Gietl, A. F. (2024) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2024.03.007 · Cited by 2 · see citing works
Amyloid spatial extent with florbetapir-PET for early detection of preclinical Alzheimer’s disease
Thibault, E. G., Montenegro, G. A. D. C., Becker, J. A., Price, J. C., Healy, B. C., Hanseeuw, B. J., Buckley, R. F., Jacobs, H. I. L., Properzi, M. J., Sperling, R. A., et al. (2026) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2026.100529 · Cited by 1 · see citing works
“Our findings align with growing evidence that A β acts as a global permissive factor necessary for the spread of tau into the neocortex [64,65].”
Šprung, J., Laporta, M. L., Knopman, D. S., Petersen, R. C., Mielke, M. M., Jack, C. R., Martin, D. P., Hanson, A. C., Schroeder, D. R., Schulte, P. J., et al. (2022) · The Journals of Gerontology Series A · doi:10.1093/gerona/glac064
Self-citationCherdak, M. A. (2023) · Advances in Gerontology · doi:10.1134/s2079057024600198
CHARACTERIZATION OF AZIDE-INDUCED EXPERIMENTAL DEMENTIA OF THE ALZHEIMER'S TYPE
Nevmerzhytska, N. M. (2024) · Bulletin of Problems Biology and Medicine · doi:10.29254/2523-4110-2024-2-173/addition-69-70
Trelle, A. N., Sheng, J., Wilson, E. N., Romero, A., Park, J., Deutsch, G. K., Sha, S. J., Greicius, M. D., Andreasson, K. I., Kerchner, G. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.20.660774
Characterizing amyloid and tau PET-based stages across the clinical continuumPreprint
Cody, K. A., Sokołowski, A., Johns, E., Guerra, L. M., Winer, J. R., Young, C. B., Younes, K., Dumitrescu, L. C., Archer, D. B., Durant, A., et al. (2025) · medRxiv · doi:10.1101/2025.09.26.25336751
Cai, Y., Du, J., Li, A., Zhu, Y., Xu, L., Sun, K., Ma, S., & Guo, T. (2024) · Figshare · doi:10.6084/m9.figshare.26567042
O’Connor, A., Cash, D. M., Poole, T., Markiewicz, P. J., Fraser, M. R., Malone, I. B., Jiao, J., Weston, P. S. J., Flores, S. E., Hornbeck, R. C., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23208001
Oxidative Stress and Pathophysiology of Chronic Disease
Balaji, S., Pandian, M. S., Ganesamoorthy, R., Parameswari, R., & Babujanarthanam, R. (2026) · Springer eBooks · doi:10.1007/978-981-96-9670-3_3
Recent Insights Into Alzheimer's Disease: Advances in Pathophysiology and Therapeutic Strategies
Shi, J., Cummings, J. L., Touchon, J., et al. (2026) · Brain Health · doi:10.1002/brh2.70004
Zhang, W., Raghavan, S., Tian, J., Przybelski, S. A., Wiste, H. J., Fought, A. J., Senjem, M. L., Schwarz, C. G., Reid, R. I., Machulda, M. M., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70707-6 · Cited by 1 · see citing works
Self-citationRudolph, M. D., Lockhart, S. N., Rundle, M. M., Barcus, R. A., Alphin, K. H., Bateman, J. R., Sai, K. K. S., Mielke, M. M., Register, T. C., Craft, S., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71483
Self-citationWu, Y., Zhang, C., Yan, J., Lin, L., Tian, Y., Fu, Z., & Sun, X. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1832525
Czech, J., Weyland, C. S., Neumann, M., Drzezga, A. E., & Schulz, J. B. (2026) · Springer eBooks · doi:10.1007/978-3-032-13040-2_6
Does CSF testing add value after an indeterminate plasma p-tau217 result?Preprint
Bernardi, E., Arranz, J., Rubio‐Guerra, S., Castro, J. G., Maure‐Blesa, L., Rodríguez‐Baz, Í., Peris‐Subiza, J., Selma‐González, J., Vera-Campuzano, E., Vaqué‐Alcázar, L., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-10754560/v1
- Authors
- Knopman, D. S., Lundt, E. S., Therneau, T. M., Albertson, S. M., Gunter, J. L., Senjem, M. L., Schwarz, C. G., Mielke, M. M., Machulda, M. M., Boeve, B. F., Jones, D. T., Graff-Radford, J., Vemuri, P., Kantarci, K., Lowe, V. J., Petersen, R. C., Jack, C. R., & Initiative, A. D. N.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Knopman, David S.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2021-02-01
- Volume
- 78
- Issue
- 2
- Pages
- 217
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC7573795
- OpenAlex
- W3092829183
- Cited by
- 61
- References
- 38
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 10 · 2023: 13 · 2022: 9 · 2021: 7
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Civil War Book Review (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
- Foundation for the National Institutes of Health (W81XWH-12-2-0012, P30 AG062677, P50 AG016574, U01 AG006786, U01AG024904, R01AG034676, AG016574, AG024904)
- Mayo Clinic (P30 AG062677, P50 AG016574, U01 AG006786, R01AG034676)
- Alzheimer's Association (U01 AG024904, W81XWH-12-2-0012)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Brigham and Women's Hospital
- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- University of Southern California (W81XWH-12-2-0012, U01 AG024904)
- Brown University
- University of Pennsylvania
- F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Mayo Foundation for Medical Education and Research (AG034676, AG016574, R01-AG034676)
- Northwestern University
- Yeshiva University
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- University of Washington
- University of Pittsburgh
- Georgetown University
- University of Rochester
- Rush University
- Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
- Little Family Foundation
- GHR Foundation (R01 AG034676)
- Elsie and Marvin Dekelboum Family Foundation
- University of Oxford
- Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Schuler-Stiftung
- National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, AG016574, AG11378, U01-AG024904, AG024904, AG062677, UL1TR002369)
- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Albert Einstein College of Medicine, Yeshiva University
- University of California, San Diego
- Perelman School of Medicine, University of Pennsylvania
- University of California, Irvine
- Medical Center, University of Rochester
- Avid Radiopharmaceuticals (AV-1451)
- Tau Consortium
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012, P50 AG016574)
- National Institute on Aging (U01-AG-024904, R01AG034676, AG-034676, W81XWH-12-2–0012, AG016574, AG 024904, U01AG006786, AG-006786, R37AG11378, R01AG011378, R01 AG41851, AG-11378, RF1AG055151, RF1AG057547, R33AG058738, R01AG041851, R37AG011378, R01AG056366, P30AG062677, P50AG016574)
- National Institute of Mental Health (U01 AG024904, W81XWH-12-2-0012)
- National Cancer Institute
- National Institute on Deafness and Other Communication Disorders
- National Institute of Neurological Disorders and Stroke (R01NS097495)
- National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- amyloid-beta, tau accumulation, flortaucipir PET, 11C-Pittsburgh compound B, Alzheimer's disease, cognitively unimpaired older adults, entorhinal cortex, clinical trial outcome measures, Mayo Clinic Study of Aging, ADNI, amyloid PET quantification
- MeSH terms
- Aged, Aged, 80 and over, Brain, Carbolines, Contrast Media, Female, Humans, Male, Cohort Studies, Amyloid beta-Peptides, Positron-Emission Tomography, Cognitive Dysfunction
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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