Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading

Alzheimer’s Disease Neuroimaging Initiative

doi:10.1016/j.neuron.2022.03.034

Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading

Alzheimer’s Disease Neuroimaging Initiative

Department of Neurology

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.

Original language	English
Pages (from-to)	1932-1943.e5
Journal	Neuron
Volume	110
Issue number	12
DOIs	https://doi.org/10.1016/j.neuron.2022.03.034
Publication status	Published - 2022 Jun 15

Bibliographical note

Funding Information:
Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904 ) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012 ). ADNI is funded by the National Institute on Aging , the National Institute of Biomedical Imaging and Bioengineering , and through generous contributions from the following: AbbVie ; Alzheimer's Association ; Alzheimer's Drug Discovery Foundation ; Araclon Biotech ; BioClinica, Inc. ; Biogen ; Bristol-Myers Squibb Company ; CereSpir, Inc. ; Cogstate ; Eisai Inc. ; Elan Pharmaceuticals, Inc. ; Eli Lilly and Company ; EuroImmun ; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc. ; Fujirebio ; GE Healthcare ; IXICO Ltd. ; Janssen Alzheimer Immunotherapy Research & Development, LLC ; Johnson & Johnson Pharmaceutical Research & Development LLC ; Lumosity ; Lundbeck ; Merck & Co., Inc. ; Meso Scale Diagnostics, LLC ; NeuroRx Research ; Neurotrack Technologies ; Novartis Pharmaceuticals Corporation ; Pfizer Inc. ; Piramal Imaging ; Servier ; Takeda Pharmaceutical Company ; and Transition Therapeutics . The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California.

Funding Information:
This work was partly supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government ( MSIP ) (no. 2019R1A2C109021211 , NRF2020R1F1A1076154 , NRF2020R1C1C1014725 , & NRF2018R1D1A1B07049386 ), Yonsei University College of Medicine grant 6-2021-0094 , the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean Government ( MSIT ) (no. 2019-0-00079 , Department of Artificial Intelligence [Korea University] ), Korea Health Industry Development Institute ( HU20C0164 ), and by NIH grants AG019724 , AG062422 , AG055698 , and AG065501 .

Funding Information:
Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co. Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. This work was partly supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (no. 2019R1A2C109021211, NRF2020R1F1A1076154, NRF2020R1C1C1014725, & NRF2018R1D1A1B07049386), Yonsei University College of Medicine grant 6-2021-0094, the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean Government (MSIT) (no. 2019-0-00079, Department of Artificial Intelligence [Korea University]), Korea Health Industry Development Institute (HU20C0164), and by NIH grants AG019724, AG062422, AG055698, and AG065501. W.J.L. J.-K.S. and W.W.S. conceived and designed the study. W.J.L. H.R.K. H.C. and C.H.L. contributed to data acquisition and processing. W.J.L. performed the experimental work, and W.J.L. J.A.B. J.-K.S. and W.W.S. analyzed and interpreted the results. W.J.L. J.A.B. J.-K.S. and W.W.S. wrote the manuscript, and J.-K.S. and W.W.S. substantively revised it. All authors participated in the discussion and critically reviewed the paper. W.W.S. received compensation as a lecturer for Corcept Therapeutics and as a consultant for Guidepoint Global Consulting and GLG Council. G.D.R. receives research support from the National Institutes of Health, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, gift from Edward and Pearl Fein, Avid Radiopharmaceuticals, Eli Lilly, Life Molecular Imaging, GE Healthcare, and Genentech. He has served as a consultant for Axon Neurosciences, Eisai, GE Healthcare, Merck, Genentech, and Roche. He serves on a data safety monitoring board for Johnson & Johnson. He is an Associate Editor for JAMA Neurology. A subset of the authors has filed provisional patent no. 63/085,749 in the U.S. based on this work.

Publisher Copyright:
© 2022 Elsevier Inc.

All Science Journal Classification (ASJC) codes

Neuroscience(all)

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10.1016/j.neuron.2022.03.034

Cite this

@article{8586a2cf040e42eaa5c8dacbf0b667fd,

title = "Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading",

abstract = "Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.",

author = "{Alzheimer{\textquoteright}s Disease Neuroimaging Initiative} and Lee, {Wha Jin} and Brown, {Jesse A.} and Kim, {Hye Ryun} and {La Joie}, Renaud and Hanna Cho and Lyoo, {Chul Hyoung} and Rabinovici, {Gil D.} and Seong, {Joon Kyung} and Seeley, {William W.}",

note = "Funding Information: Data collection and sharing for this project was funded by the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904 ) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012 ). ADNI is funded by the National Institute on Aging , the National Institute of Biomedical Imaging and Bioengineering , and through generous contributions from the following: AbbVie ; Alzheimer's Association ; Alzheimer's Drug Discovery Foundation ; Araclon Biotech ; BioClinica, Inc. ; Biogen ; Bristol-Myers Squibb Company ; CereSpir, Inc. ; Cogstate ; Eisai Inc. ; Elan Pharmaceuticals, Inc. ; Eli Lilly and Company ; EuroImmun ; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc. ; Fujirebio ; GE Healthcare ; IXICO Ltd. ; Janssen Alzheimer Immunotherapy Research & Development, LLC ; Johnson & Johnson Pharmaceutical Research & Development LLC ; Lumosity ; Lundbeck ; Merck & Co., Inc. ; Meso Scale Diagnostics, LLC ; NeuroRx Research ; Neurotrack Technologies ; Novartis Pharmaceuticals Corporation ; Pfizer Inc. ; Piramal Imaging ; Servier ; Takeda Pharmaceutical Company ; and Transition Therapeutics . The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. Funding Information: This work was partly supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government ( MSIP ) (no. 2019R1A2C109021211 , NRF2020R1F1A1076154 , NRF2020R1C1C1014725 , & NRF2018R1D1A1B07049386 ), Yonsei University College of Medicine grant 6-2021-0094 , the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean Government ( MSIT ) (no. 2019-0-00079 , Department of Artificial Intelligence [Korea University] ), Korea Health Industry Development Institute ( HU20C0164 ), and by NIH grants AG019724 , AG062422 , AG055698 , and AG065501 . Funding Information: Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co. Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. This work was partly supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (no. 2019R1A2C109021211, NRF2020R1F1A1076154, NRF2020R1C1C1014725, & NRF2018R1D1A1B07049386), Yonsei University College of Medicine grant 6-2021-0094, the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean Government (MSIT) (no. 2019-0-00079, Department of Artificial Intelligence [Korea University]), Korea Health Industry Development Institute (HU20C0164), and by NIH grants AG019724, AG062422, AG055698, and AG065501. W.J.L. J.-K.S. and W.W.S. conceived and designed the study. W.J.L. H.R.K. H.C. and C.H.L. contributed to data acquisition and processing. W.J.L. performed the experimental work, and W.J.L. J.A.B. J.-K.S. and W.W.S. analyzed and interpreted the results. W.J.L. J.A.B. J.-K.S. and W.W.S. wrote the manuscript, and J.-K.S. and W.W.S. substantively revised it. All authors participated in the discussion and critically reviewed the paper. W.W.S. received compensation as a lecturer for Corcept Therapeutics and as a consultant for Guidepoint Global Consulting and GLG Council. G.D.R. receives research support from the National Institutes of Health, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, gift from Edward and Pearl Fein, Avid Radiopharmaceuticals, Eli Lilly, Life Molecular Imaging, GE Healthcare, and Genentech. He has served as a consultant for Axon Neurosciences, Eisai, GE Healthcare, Merck, Genentech, and Roche. He serves on a data safety monitoring board for Johnson & Johnson. He is an Associate Editor for JAMA Neurology. A subset of the authors has filed provisional patent no. 63/085,749 in the U.S. based on this work. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = jun,

day = "15",

doi = "10.1016/j.neuron.2022.03.034",

language = "English",

volume = "110",

pages = "1932--1943.e5",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "12",

}

TY - JOUR

T1 - Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading

AU - Alzheimer’s Disease Neuroimaging Initiative

AU - Lee, Wha Jin

AU - Brown, Jesse A.

AU - Kim, Hye Ryun

AU - La Joie, Renaud

AU - Cho, Hanna

AU - Lyoo, Chul Hyoung

AU - Rabinovici, Gil D.

AU - Seong, Joon Kyung

AU - Seeley, William W.

N1 - Funding Information: Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904 ) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012 ). ADNI is funded by the National Institute on Aging , the National Institute of Biomedical Imaging and Bioengineering , and through generous contributions from the following: AbbVie ; Alzheimer's Association ; Alzheimer's Drug Discovery Foundation ; Araclon Biotech ; BioClinica, Inc. ; Biogen ; Bristol-Myers Squibb Company ; CereSpir, Inc. ; Cogstate ; Eisai Inc. ; Elan Pharmaceuticals, Inc. ; Eli Lilly and Company ; EuroImmun ; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc. ; Fujirebio ; GE Healthcare ; IXICO Ltd. ; Janssen Alzheimer Immunotherapy Research & Development, LLC ; Johnson & Johnson Pharmaceutical Research & Development LLC ; Lumosity ; Lundbeck ; Merck & Co., Inc. ; Meso Scale Diagnostics, LLC ; NeuroRx Research ; Neurotrack Technologies ; Novartis Pharmaceuticals Corporation ; Pfizer Inc. ; Piramal Imaging ; Servier ; Takeda Pharmaceutical Company ; and Transition Therapeutics . The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. Funding Information: This work was partly supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government ( MSIP ) (no. 2019R1A2C109021211 , NRF2020R1F1A1076154 , NRF2020R1C1C1014725 , & NRF2018R1D1A1B07049386 ), Yonsei University College of Medicine grant 6-2021-0094 , the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean Government ( MSIT ) (no. 2019-0-00079 , Department of Artificial Intelligence [Korea University] ), Korea Health Industry Development Institute ( HU20C0164 ), and by NIH grants AG019724 , AG062422 , AG055698 , and AG065501 . Funding Information: Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co. Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. This work was partly supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (no. 2019R1A2C109021211, NRF2020R1F1A1076154, NRF2020R1C1C1014725, & NRF2018R1D1A1B07049386), Yonsei University College of Medicine grant 6-2021-0094, the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean Government (MSIT) (no. 2019-0-00079, Department of Artificial Intelligence [Korea University]), Korea Health Industry Development Institute (HU20C0164), and by NIH grants AG019724, AG062422, AG055698, and AG065501. W.J.L. J.-K.S. and W.W.S. conceived and designed the study. W.J.L. H.R.K. H.C. and C.H.L. contributed to data acquisition and processing. W.J.L. performed the experimental work, and W.J.L. J.A.B. J.-K.S. and W.W.S. analyzed and interpreted the results. W.J.L. J.A.B. J.-K.S. and W.W.S. wrote the manuscript, and J.-K.S. and W.W.S. substantively revised it. All authors participated in the discussion and critically reviewed the paper. W.W.S. received compensation as a lecturer for Corcept Therapeutics and as a consultant for Guidepoint Global Consulting and GLG Council. G.D.R. receives research support from the National Institutes of Health, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, gift from Edward and Pearl Fein, Avid Radiopharmaceuticals, Eli Lilly, Life Molecular Imaging, GE Healthcare, and Genentech. He has served as a consultant for Axon Neurosciences, Eisai, GE Healthcare, Merck, Genentech, and Roche. He serves on a data safety monitoring board for Johnson & Johnson. He is an Associate Editor for JAMA Neurology. A subset of the authors has filed provisional patent no. 63/085,749 in the U.S. based on this work. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/6/15

Y1 - 2022/6/15

N2 - Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.

AB - Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.

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DO - 10.1016/j.neuron.2022.03.034

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AN - SCOPUS:85129973233

SN - 0896-6273

VL - 110

SP - 1932-1943.e5

JO - Neuron

JF - Neuron

IS - 12

ER -

Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading

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