Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease
Open accessAbstract
SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-β) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that (18)F-AV1451 and (18)F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F-FDG uptake (Pearson's r = -0.49 ± 0.07, P < 0.001) and less pronounced positive associations between (11)C-PiB and (18)F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and (18)F-AV1451 and (11)C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater (18)F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased (18)F-AV1451 in the medial temporal lobe. APOE ϵ4 carriers showed greater temporal and parietal (18)F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater (18)F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.
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Tau PET is an excellent indicator of symptomatic AD.
“Because tau PET is an excellent indicator of symptomatic AD5”
From Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests (2024) · cites this paper as [5]
In a cohort of 20 AD and 15 controls, regional tau PET deposition co-localised with hypometabolic regions and correlated with areas critical for cognitive functions uniquely affected in distinct variants of AD.
“In a cohort of 20 AD and 15 controls who underwent 18F-flortaucipir, 11C-PiB and FDG-PET, regional tau PET deposition co-localised with hypometabolic regions and correlated with areas critical for cognitive functions uniquely affected in distinct variants of AD (e.g. posterior cortical atrophy) [191].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [191]
Overall, tau PET deposition mirrors progression of AD pathology and correlates with disease severity.
“Overall, tau PET deposition mirrors the progression of AD pathology, correlates with disease severity and in that respect it is hypothesised that will become one of the most important tools for the differential diagnosis between AD and non-AD dementias [191, 199, 200].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [191]
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Self-citationDistinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease
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Self-citation18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes
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Self-citationA clinical-radiological framework of the right temporal variant of frontotemporal dementia
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Self-citationOssenkoppele, R., Lyoo, C. H., Jester-Broms, J., Sudre, C. H., Cho, H., Ryu, Y. H., Choi, J. Y., Smith, R., Strandberg, O., Palmqvist, S., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2019.5154 · Cited by 161 · see citing works
Townley, R. A., Graff-Radford, J., Mantyh, W. G., Botha, H., Polsinelli, A. J., Przybelski, S. A., Machulda, M. M., Makhlouf, A. T., Senjem, M. L., Murray, M. E., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa068 · Cited by 145 · see citing works
Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
Leuzy, A., Smith, R., Cullen, N. C., Strandberg, O., Vogel, J. W., Binette, A. P., Borroni, E., Janelidze, S., Ohlsson, T., Jögi, J., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2021.4654 · Cited by 149 · see citing works
Self-citationThe Alzheimer’s disease drug development landscape
van Bokhoven, P., de Wilde, A., Vermunt, L., Leferink, P. S., Heetveld, S., Cummings, J., Scheltens, P., & Vijverberg, E. G. B. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00927-z · Cited by 123 · see citing works
Fluorodeoxyglucose metabolism associated with tau‐amyloid interaction predicts memory decline
Hanseeuw, B. J., Betensky, R. A., Schultz, A. P., Papp, K. V., Mormino, E. C., Sepulcre, J., Bark, J. S., Cosio, D. M., LaPoint, M., Chhatwal, J. P., et al. (2017) · Annals of Neurology · doi:10.1002/ana.24910 · Cited by 140 · see citing works
Hall, B., Mak, E., Cervenka, S., Aigbirhio, F. I., Rowe, J. B., & O’Brien, J. T. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.03.002 · Cited by 132 · see citing works
Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits
Koutsodendris, N., Blumenfeld, J., Agrawal, A., Traglia, M., Grone, B., Zilberter, M., Yip, O., Rao, A., Nelson, M. R., Hao, Y., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00368-3 · Cited by 132 · see citing works
Predicting future rates of tau accumulation on PET
Jack, C. R., Wiste, H. J., Weigand, S. D., Therneau, T. M., Lowe, V. J., Knopman, D. S., Botha, H., Graff-Radford, J., Jones, D. T., Ferman, T. J., et al. (2020) · Brain · doi:10.1093/brain/awaa248 · Cited by 117 · see citing works
Parker, T. D., Slattery, C. F., Zhang, J., Nicholas, J. M., Paterson, R. W., Foulkes, A. J. M., Malone, I. B., Thomas, D. L., Modat, M., Cash, D. M., et al. (2018) · Human Brain Mapping · doi:10.1002/hbm.24056 · Cited by 122 · see citing works
Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults
Lowe, V. J., Bruinsma, T. J., Wiste, H. J., Min, H.-K., Weigand, S. D., Fang, P., Senjem, M. L., Therneau, T. M., Boeve, B. F., Josephs, K. A., et al. (2019) · Neurology · doi:10.1212/wnl.0000000000007728 · Cited by 107 · see citing works
Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases
(2020) · International Review of Neurobiology · doi:10.1016/bs.irn.2020.03.019 · Cited by 114 · see citing works
Diagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability
Therriault, J., Janelidze, S., Benedet, A. L., Ashton, N. J., Arranz Martínez, J., Gonzalez-Escalante, A., Bellaver, B., Alcolea, D., Vrillon, A., Karim, H., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00731-y · Cited by 112 · see citing works
“Overall, however, plasma biomarkers are more limited in ruling in AD pathology in non-AD clinical syndromes and follow-up testing with either PET or CSF may be warranted; in these instances, the topographical information provided by tau-PET 47,48 may be useful.”
The informed road map to prevention of Alzheimer Disease: a call to arms
McDade, E., Llibre-Guerra, J. J., Holtzman, D. M., Morris, J. C., & Bateman, R. J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00467-y · Cited by 89 · see citing works
PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research
Bao, W., Xie, F., Zuo, C., Guan, Y., & Huang, Y. H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.624330 · Cited by 102 · see citing works
Correlation of In Vivo [<sup>18</sup>F]Flortaucipir With Postmortem Alzheimer Disease Tau Pathology
Smith, R., Wibom, M., Pawlik, D., Englund, E., & Hansson, O. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2018.3692 · Cited by 111 · see citing works
Alzheimer's drug‐development pipeline: 2016
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“The availability of tau imaging and the consistent relationships shown between tau signals on imaging and the clinical state of the individual indicate that tau is an important target for drug development and that tau imaging may serve as a useful biomarker to help guide drug development [17–20].”
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Flortaucipir tau PET imaging in semantic variant primary progressive aphasia
Makaretz, S. J., Quimby, M., Collins, J., Makris, N., McGinnis, S., Schultz, A., Vasdev, N., Johnson, K. A., & Dickerson, B. C. (2018) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-316409 · Cited by 104 · see citing works
Beyond the average patient: how neuroimaging models can address heterogeneity in dementia
Verdi, S., Marquand, A. F., Schott, J. M., & Cole, J. H. (2021) · Brain · doi:10.1093/brain/awab165 · Cited by 106 · see citing works
ApoE influences regional white-matter axonal density loss in Alzheimer's disease
Slattery, C. F., Zhang, J., Paterson, R. W., Foulkes, A. J. M., Carton, A., Macpherson, K., Mancini, L., Thomas, D. L., Modat, M., Toussaint, N., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.04.021 · Cited by 102 · see citing works
Heterogeneity of Alzheimer’s disease: consequence for drug trials?
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Targeting tau: clinical trials and novel therapeutic approaches
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In vivo synaptic density loss is related to tau deposition in amnestic mild cognitive impairment
Vanhaute, H., Ceccarini, J., Michiels, L., Koole, M., Sunaert, S., Lemmens, R., Triau, E., Emsell, L., Vandenbulcke, M., & Van Laere, K. (2020) · Neurology · doi:10.1212/wnl.0000000000009818 · Cited by 88 · see citing works
Progressive Tau Accumulation in Alzheimer Disease: 2-Year Follow-up Study
Cho, H., Choi, J. Y., Lee, H. S., Lee, J. H., Ryu, Y. H., Lee, M. S., Jack, C. R., & Lyoo, C. H. (2019) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.221697 · Cited by 94 · see citing works
Mattsson, N., Insel, P. S., Donohue, M., Jögi, J., Ossenkoppele, R., Olsson, T., Schöll, M., Smith, R., & Hansson, O. (2019) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.12.001 · Cited by 92 · see citing works
Self-citationStaffaroni, A., Elahi, F., McDermott, D., Marton, K., Karageorgiou, E., Sacco, S., Paoletti, M., Caverzasi, E., Hess, C., Rosen, H., et al. (2017) · Seminars in Neurology · doi:10.1055/s-0037-1608808 · Cited by 91 · see citing works
Bevan-Jones, W. R., Cope, T. E., Jones, P. S., Passamonti, L., Hong, Y. T., Fryer, T. D., Arnold, R., Allinson, K. S. J., Coles, J. P., Aigbirhio, F. I., et al. (2018) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-316402 · Cited by 84 · see citing works
Wattmo, C., Blennow, K., & Hansson, O. (2020) · BMC Neurology · doi:10.1186/s12883-019-1591-0 · Cited by 93 · see citing works
Head-to-head comparison of tau positron emission tomography tracers [18F]flortaucipir and [18F]RO948
Smith, R., Schöll, M., Leuzy, A., Jögi, J., Ohlsson, T., Strandberg, O., & Hansson, O. (2020) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04496-0 · Cited by 88 · see citing works
Self-citationYoung, C. B., Winer, J. R., Younes, K., Cody, K. A., Betthauser, T. J., Johnson, S. C., Schultz, A., Sperling, R. A., Greicius, M. D., Cobos, I., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.0676 · Cited by 79 · see citing works
Self-citationAdvances in Alzheimer's disease research over the past two decades
Jack, C. R. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00298-8 · Cited by 83 · see citing works
Tetzloff, K. A., Graff-Radford, J., Martin, P. R., Tosakulwong, N., Machulda, M. M., Duffy, J. R., Clark, H. M., Senjem, M. L., Schwarz, C. G., Spychalla, A. J., et al. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170740 · Cited by 78 · see citing works
Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation
Saroja, S. R., Gorbachev, K., Julia, T., Goate, A. M., & Pereira, A. C. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2108870119 · Cited by 75 · see citing works
Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease
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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., et al. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2020.3921 · Cited by 61 · see citing works
Does inflammation precede tau aggregation in early Alzheimer's disease? A PET study
Parbo, P., Ismail, R., Sommerauer, M., Stokholm, M. G., Hansen, A. K., Hansen, K. V., Amidi, A., Schaldemose, J. L., Gottrup, H., Brændgaard, H., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.06.004 · Cited by 63 · see citing works
Diagnosis and Management of Posterior Cortical Atrophy
Yong, K. X. X., Graff-Radford, J., Ahmed, S., Chapleau, M., Ossenkoppele, R., Putcha, D., Rabinovici, G. D., Suarez-Gonzalez, A., Schott, J. M., Crutch, S., et al. (2023) · Current Treatment Options in Neurology · doi:10.1007/s11940-022-00745-0 · Cited by 51 · see citing works
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Gray Matter Network Disruptions and Regional Amyloid Beta in Cognitively Normal Adults
ten Kate, M., Visser, P. J., Bakardjian, H., Barkhof, F., Sikkes, S. A. M., van der Flier, W. M., Scheltens, P., Hampel, H., Habert, M.-O., Dubois, B., et al. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00067 · Cited by 41 · see citing works
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Functional network segregation is associated with attenuated tau spreading in Alzheimer's disease
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Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data
Karlsson, L., Vogel, J., Arvidsson, I., Åström, K., Strandberg, O., Seidlitz, J., Bethlehem, R. A. I., Stomrud, E., Ossenkoppele, R., Ashton, N. J., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.14600 · Cited by 43 · see citing works
Self-citationProgress and challenges in the diagnosis of dementia: a critical review
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In vivo [ <sup>18</sup> F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease
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Distinct tau PET imaging patterns in typical and atypical Alzheimer’s disease
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- Authors
- Ossenkoppele, R., Schonhaut, D. R., Schöll, M., Lockhart, S. N., Ayakta, N., Baker, S. L., O’Neil, J. P., Janabi, M., Lazaris, A., Cantwell, A., Vogel, J., Santos, M., Miller, Z. A., Bettcher, B. M., Vossel, K. A., Kramer, J. H., Gorno-Tempini, M. L., Miller, B. L., Jagust, W. J., & Rabinovici, G. D.
- Affiliations
- University of California, San Francisco (US)
- University of Gothenburg (SE)
- University of California, Berkeley (US)
- Lawrence Berkeley National Laboratory (US)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-03-08
- Volume
- 139
- Issue
- 5
- Pages
- 1551-1567
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5006248
- OpenAlex
- W2293378393
- Cited by
- 1,185
- References
- 19
- Citations by year
- 2026: 95 · 2025: 125 · 2024: 120 · 2023: 105 · 2022: 137 · 2021: 123 · 2020: 131 · 2019: 115 · 2018: 103 · 2017: 96 · 2016: 33
- FWCI
- 102.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- BrightFocus Foundation
- European Commission (628812)
- Sveriges Läkarförbund
- University of California, San Francisco
- Avid Radiopharmaceuticals
- National Institute on Aging (K23AG038357, F32AG050389, R01AG045611, K23AG042492, K23AG048291, P01AG019724, R01AG034570, P50AG023501)
- 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
- Alzheimer's disease, tau PET, 18F-AV-1451, amyloid PET, [11C]PIB, posterior cortical atrophy, logopenic variant primary progressive aphasia, clinical phenotype
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Amyloid, Aniline Compounds, Apolipoproteins E, Brain, Carbolines, Female, Glucose, Humans, Male, Middle Aged, Neuropsychological Tests, Thiazoles, Case-Control Studies, tau Proteins, Fluorodeoxyglucose F18, Positron-Emission Tomography, Benzothiazoles, Neuroimaging, Cognitive Dysfunction
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