Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

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19 Scopus citations

Abstract

Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (NM) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/NM clusters with differing limbic and cortical patterns. The canonical group was defined as the T/NM pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/NM mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD.

Original languageEnglish
Article number1495
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Funding

This work presented in this manuscript was funded by the University of Pennsylvania Alzheimer’s Disease Core Center grant (National Institute on Aging P30 AG072979). The authors thank our lab members for helpful discussions and the ADNI/HABS investigators, staff, participants and families for their support. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A listing of ADNI consortium investigators can be found at the end of the article. Data collection and sharing for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was funded by the National Institutes of Health (NIH U01 AG024904) and the Department of Defense (DOD ADNI 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 ADNI 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 NeuroImaging at the University of Southern California. Additional data used in the preparation of this article were obtained from the Harvard Aging Brain Study (HABS—P01AG036694; https://habs.mgh.harvard.edu). HABS was launched in 2010, funded by the National Institute on Aging. and is led by principal investigators R.A.S., MD and K.A.J., MD at Massachusetts General Hospital/Harvard Medical School in Boston, MA. This work presented in this manuscript was funded by the University of Pennsylvania Alzheimer’s Disease Core Center grant (National Institute on Aging P30 AG072979). The authors thank our lab members for helpful discussions and the ADNI/HABS investigators, staff, participants and families for their support. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database ( adni.loni.usc.edu ). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A listing of ADNI consortium investigators can be found at the end of the article. Data collection and sharing for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was funded by the National Institutes of Health (NIH U01 AG024904) and the Department of Defense (DOD ADNI 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 ADNI 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 NeuroImaging at the University of Southern California. Additional data used in the preparation of this article were obtained from the Harvard Aging Brain Study (HABS—P01AG036694; https://habs.mgh.harvard.edu ). HABS was launched in 2010, funded by the National Institute on Aging. and is led by principal investigators R.A.S., MD and K.A.J., MD at Massachusetts General Hospital/Harvard Medical School in Boston, MA.

FundersFunder number
DOD ADNIW81XWH-12-2-0012
Harvard Aging Brain StudyHABS—P01AG036694
University of Pennsylvania Alzheimer’s Disease Core Center
National Institutes of Health (NIH)U01 AG024904
National Institutes of Health (NIH)
U.S. Department of Defense
National Institute on AgingRF1AG069474, P30 AG072979
National Institute on Aging
National Institute of Biomedical Imaging and Bioengineering
University of Southern California
DoD Alzheimer's Disease Neuroimaging Initiative

    ASJC Scopus subject areas

    • General Chemistry
    • General Biochemistry, Genetics and Molecular Biology
    • General Physics and Astronomy

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