Local molecular and connectomic contributions of tau-related neurodegeneration

doi:10.1007/s11357-024-01339-1

Local molecular and connectomic contributions of tau-related neurodegeneration

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

2 Scopus citations

Abstract

Neurodegeneration in Alzheimer’s disease (AD) is known to be mostly driven by tau neurofibrillary tangles. However, both tau and neurodegeneration exhibit variability in their distribution across the brain and among individuals, and the relationship between tau and neurodegeneration might be influenced by several factors. I aimed to map local molecular and connectivity characteristics that affect the association between tau pathology and neurodegeneration. The current study was conducted on the cross-sectional tau-PET and longitudinal T1-weighted MRI scan data of 186 participants from the ADNI dataset including 71 cognitively unimpaired (CU) and 115 mild cognitive impairment (MCI) individuals. Furthermore, the normative molecular profile of a region was defined using neurotransmitter receptor densities, gene expression, T1w/T2w ratio (myelination), FDG-PET (glycolytic index, glucose metabolism, and oxygen metabolism), and synaptic density. I found that the excitatory-inhibitory (E:I) ratio, myelination, synaptic density, glycolytic index, and functional connectivity are linked with deviation in the relationship between tau and neurodegeneration. Furthermore, there was spatial similarity between tau pathology and glycolytic index, synaptic density, and functional connectivity across brain regions. The current study demonstrates that the regional susceptibility to tau-related neurodegeneration is associated with specific molecular and connectomic characteristics of the affected neural systems. I found that the molecular and connectivity architecture of the human brain is linked to the different effects of tau pathology on downstream neurodegeneration.

Original language	English
Pages (from-to)	227-246
Number of pages	20
Journal	GeroScience
Volume	47
Issue number	1
DOIs	https://doi.org/10.1007/s11357-024-01339-1
State	Published - Feb 2025

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to American Aging Association 2024.

Funding

Data collection and sharing for this project were provided 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 for Neuro Imaging at the University of Southern California. Consortia Alzheimer’s Disease Neuroimaging Initiative Michael W. Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowski, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Lew Kuller, Marcus Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, Marek M. Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Matthew Bernstein, Paul Thompson, Norbert Schuff, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven G. Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Leon Thal, Neil Buckholtz, Marylyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Sue Leon, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, Randall Griffith, David Clark, David Geldmacher, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Leyla de Toledo-Morrell, Raj C. Shah, Ranjan Duara, Daniel Varon, Maria T. Greig, Peggy Roberts, Chiadi Onyike, Daniel D’Agostino, Stephanie Kielb, James E. Galvin, Brittany Cerbone, Christina A. Michel, Henry Rusinek, Mony J. de Leon, Lidia Glodzik, Susan De Santi, PMurali Doraiswamy, Jeffrey R. Petrella, Terence Z. Wong, Steven E. Arnold, Jason H. Karlawish, David Wolk, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, MSaleem Ismail, Connie Brand, Ruth A. Mulnard, Gaby Thai, Catherine McAdams-Ortiz, Kyle Womack, Dana Mathews, Mary Quiceno, Ramon Diaz-Arrastia, Richard King, Myron Weiner, Kristen Martin-Cook, Michael DeVous, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Heather S. Anderson, Russell H. Swerdlow, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H. S. Silverman, Po H. Lu, George Bartzokis, Neill R. Graff-Radford, Francine Parfitt, Tracy Kendall, Heather Johnson, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Scott Herring, Cynthia Hunt, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Howard Chertkow, Howard Bergman, Chris Hosein, Ging-Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly, Charles Bernick, Donna Munic, Andrew Kertesz, John Rogers, Dick Trost, Diana Kerwin, Kristine Lipowski, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Meghan Frey, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Joanne Allard, Alan Lerner, Paula Ogrocki, Leon Hudson, Evan Fletcher, Owen Carmichae, John Olichney, Charles DeCarli, Smita Kittur, Michael Borrie, T.-Y. Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Adrian Preda, Dana Nguyen, Pierre Tariot, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Anahita Adeli, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Robert B. Santulli, Tamar J. Kitzmiller, Eben S. Schwartz, Kaycee M. Sink, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Laura L. Boles Ponto, Hyungsub Shim, Karen Elizabeth Smith, Norman Relkin, Gloria Chaing, Lisa Raudin, Amanda Smith, Kristin Fargher, Balebail Ashok Raj, Thomas Neylan, Jordan Grafman, Melissa Davis, Rosemary Morrison, Jacqueline Hayes, Shannon Finley, Karl Friedl, Debra Fleischman, Konstantinos Arfanakis, Olga James, Dino Massoglia, JJay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Joy L. Taylor, and Ansgar J. Furst. Data collection and sharing for this project were provided 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 for Neuro Imaging at the University of Southern California.

Funders	Funder number
Northern California Institute for Research and Education
John Morris Scientific
University of Southern California
Euroimmun
National Institute of Biomedical Imaging and Bioengineering
Helen Vanderswag
Andrew J. Saykin
Eli Lilly and Company
DoD Alzheimer's Disease Neuroimaging Initiative
Roche Canada
DOD ADNI
National Institute on Aging
National Institutes of Health (NIH)	U01 AG024904
National Institutes of Health (NIH)
U.S. Department of Defense	W81XWH-12-2-0012
U.S. Department of Defense

Keywords

Alzheimer’s disease
Connectivity
Mild cognitive impairment
Molecular
Neurodegeneration
Tau

ASJC Scopus subject areas

Aging
Veterinary (miscellaneous)
Complementary and alternative medicine
Geriatrics and Gerontology
Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s11357-024-01339-1

Cite this

@article{ada6b756621b458980385e9ca041512e,

title = "Local molecular and connectomic contributions of tau-related neurodegeneration",

abstract = "Neurodegeneration in Alzheimer{\textquoteright}s disease (AD) is known to be mostly driven by tau neurofibrillary tangles. However, both tau and neurodegeneration exhibit variability in their distribution across the brain and among individuals, and the relationship between tau and neurodegeneration might be influenced by several factors. I aimed to map local molecular and connectivity characteristics that affect the association between tau pathology and neurodegeneration. The current study was conducted on the cross-sectional tau-PET and longitudinal T1-weighted MRI scan data of 186 participants from the ADNI dataset including 71 cognitively unimpaired (CU) and 115 mild cognitive impairment (MCI) individuals. Furthermore, the normative molecular profile of a region was defined using neurotransmitter receptor densities, gene expression, T1w/T2w ratio (myelination), FDG-PET (glycolytic index, glucose metabolism, and oxygen metabolism), and synaptic density. I found that the excitatory-inhibitory (E:I) ratio, myelination, synaptic density, glycolytic index, and functional connectivity are linked with deviation in the relationship between tau and neurodegeneration. Furthermore, there was spatial similarity between tau pathology and glycolytic index, synaptic density, and functional connectivity across brain regions. The current study demonstrates that the regional susceptibility to tau-related neurodegeneration is associated with specific molecular and connectomic characteristics of the affected neural systems. I found that the molecular and connectivity architecture of the human brain is linked to the different effects of tau pathology on downstream neurodegeneration.",

keywords = "Alzheimer{\textquoteright}s disease, Connectivity, Mild cognitive impairment, Molecular, Neurodegeneration, Tau",

author = "Fardin Nabizadeh and Furst, \{Ansgar J.\} and Taylor, \{Joy L.\} and Yesavage, \{Jerome A.\} and Gail Li and Petrie, \{Eric C.\} and Peskind, \{Elaine R.\} and Sandra Harding and JJay Fruehling and Dino Massoglia and Olga James and Konstantinos Arfanakis and Debra Fleischman and Karl Friedl and Shannon Finley and Jacqueline Hayes and Rosemary Morrison and Melissa Davis and Jordan Grafman and Thomas Neylan and Raj, \{Balebail Ashok\} and Kristin Fargher and Amanda Smith and Lisa Raudin and Gloria Chaing and Norman Relkin and Smith, \{Karen Elizabeth\} and Hyungsub Shim and Ponto, \{Laura L.Boles\} and Schultz, \{Susan K.\} and Antero Sarrael and Raymundo Hernando and Nunzio Pomara and Dick Drost and Irina Rachinsky and Stephen Pasternak and David Bachman and Kenneth Spicer and Jacobo Mintzer and Miller, \{Bruce L.\} and Rosen, \{Howard J.\} and Stephen Correia and Paul Malloy and Stephen Salloway and Geoffrey Tremont and Henry Querfurth and Ott, \{Brian R.\} and Richard King and Greg Jicha and Toga, \{Arthur W.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to American Aging Association 2024.",

year = "2025",

month = feb,

doi = "10.1007/s11357-024-01339-1",

language = "English",

volume = "47",

pages = "227--246",

number = "1",

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AU - Nabizadeh, Fardin

AU - Furst, Ansgar J.

AU - Taylor, Joy L.

AU - Yesavage, Jerome A.

AU - Li, Gail

AU - Petrie, Eric C.

AU - Peskind, Elaine R.

AU - Harding, Sandra

AU - Fruehling, JJay

AU - Massoglia, Dino

AU - James, Olga

AU - Arfanakis, Konstantinos

AU - Fleischman, Debra

AU - Friedl, Karl

AU - Finley, Shannon

AU - Hayes, Jacqueline

AU - Morrison, Rosemary

AU - Davis, Melissa

AU - Grafman, Jordan

AU - Neylan, Thomas

AU - Raj, Balebail Ashok

AU - Fargher, Kristin

AU - Smith, Amanda

AU - Raudin, Lisa

AU - Chaing, Gloria

AU - Relkin, Norman

AU - Smith, Karen Elizabeth

AU - Shim, Hyungsub

AU - Ponto, Laura L.Boles

AU - Schultz, Susan K.

AU - Sarrael, Antero

AU - Hernando, Raymundo

AU - Pomara, Nunzio

AU - Drost, Dick

AU - Rachinsky, Irina

AU - Pasternak, Stephen

AU - Bachman, David

AU - Spicer, Kenneth

AU - Mintzer, Jacobo

AU - Miller, Bruce L.

AU - Rosen, Howard J.

AU - Correia, Stephen

AU - Malloy, Paul

AU - Salloway, Stephen

AU - Tremont, Geoffrey

AU - Querfurth, Henry

AU - Ott, Brian R.

AU - King, Richard

AU - Jicha, Greg

AU - Toga, Arthur W.

PY - 2025/2

Y1 - 2025/2

N2 - Neurodegeneration in Alzheimer’s disease (AD) is known to be mostly driven by tau neurofibrillary tangles. However, both tau and neurodegeneration exhibit variability in their distribution across the brain and among individuals, and the relationship between tau and neurodegeneration might be influenced by several factors. I aimed to map local molecular and connectivity characteristics that affect the association between tau pathology and neurodegeneration. The current study was conducted on the cross-sectional tau-PET and longitudinal T1-weighted MRI scan data of 186 participants from the ADNI dataset including 71 cognitively unimpaired (CU) and 115 mild cognitive impairment (MCI) individuals. Furthermore, the normative molecular profile of a region was defined using neurotransmitter receptor densities, gene expression, T1w/T2w ratio (myelination), FDG-PET (glycolytic index, glucose metabolism, and oxygen metabolism), and synaptic density. I found that the excitatory-inhibitory (E:I) ratio, myelination, synaptic density, glycolytic index, and functional connectivity are linked with deviation in the relationship between tau and neurodegeneration. Furthermore, there was spatial similarity between tau pathology and glycolytic index, synaptic density, and functional connectivity across brain regions. The current study demonstrates that the regional susceptibility to tau-related neurodegeneration is associated with specific molecular and connectomic characteristics of the affected neural systems. I found that the molecular and connectivity architecture of the human brain is linked to the different effects of tau pathology on downstream neurodegeneration.

AB - Neurodegeneration in Alzheimer’s disease (AD) is known to be mostly driven by tau neurofibrillary tangles. However, both tau and neurodegeneration exhibit variability in their distribution across the brain and among individuals, and the relationship between tau and neurodegeneration might be influenced by several factors. I aimed to map local molecular and connectivity characteristics that affect the association between tau pathology and neurodegeneration. The current study was conducted on the cross-sectional tau-PET and longitudinal T1-weighted MRI scan data of 186 participants from the ADNI dataset including 71 cognitively unimpaired (CU) and 115 mild cognitive impairment (MCI) individuals. Furthermore, the normative molecular profile of a region was defined using neurotransmitter receptor densities, gene expression, T1w/T2w ratio (myelination), FDG-PET (glycolytic index, glucose metabolism, and oxygen metabolism), and synaptic density. I found that the excitatory-inhibitory (E:I) ratio, myelination, synaptic density, glycolytic index, and functional connectivity are linked with deviation in the relationship between tau and neurodegeneration. Furthermore, there was spatial similarity between tau pathology and glycolytic index, synaptic density, and functional connectivity across brain regions. The current study demonstrates that the regional susceptibility to tau-related neurodegeneration is associated with specific molecular and connectomic characteristics of the affected neural systems. I found that the molecular and connectivity architecture of the human brain is linked to the different effects of tau pathology on downstream neurodegeneration.

KW - Alzheimer’s disease

KW - Connectivity

KW - Mild cognitive impairment

KW - Molecular

KW - Neurodegeneration

KW - Tau

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JO - GeroScience

JF - GeroScience

IS - 1

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Local molecular and connectomic contributions of tau-related neurodegeneration

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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