@article{069072d6dce24c2c965fb113a3258f0f,
title = "The landscape of metabolic brain alterations in Alzheimer's disease",
abstract = "Introduction: Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in the brain has been missing. Methods: We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures. Results: We observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation, and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than amyloid beta pathology. Discussion: This work provides a comprehensive reference map of metabolic brain changes in AD that lays the foundation for future mechanistic follow-up studies.",
keywords = "Alzheimer's disease, bioenergetic pathways, brain, cholesterol metabolism, metabolic landscape, metabolism, multi-omic integration, neuroinflammation, neurotransmission, osmoregulation",
author = "{for the Alzheimer's Disease Metabolomics Consortium (ADMC)} and Richa Batra and Matthias Arnold and W{\"o}rheide, {Maria A.} and Mariet Allen and Xue Wang and Colette Blach and Levey, {Allan I.} and Seyfried, {Nicholas T.} and Nil{\"u}fer Ertekin-Taner and Bennett, {David A.} and Gabi Kastenm{\"u}ller and Kaddurah-Daouk, {Rima F.} and Jan Krumsiek",
note = "Funding Information: This work was done as part of the National Institute on Aging's Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP‐AD) and was supported by NIH grants 1U19AG063744, 1R01AG069901‐01A1, U01AG061357, P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356, RF1AG058942, RF1AG059093, and U01AG061359. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.org ). The Religious Orders and the Rush Memory and Aging studies were supported by the National Institute on Aging grants P30AG10161, R01AG15819, R01AG17917, U01AG46152, and U01AG61356. The NIA also supported the Alzheimer Disease Metabolomics Consortium, which is a part of the NIA's national initiatives AMP‐AD and MOVE‐AD (R01 AG046171, RF1 AG051550, and 3U01 AG061359‐02S1). We thank the participants of ROS and MAP for their essential contributions and the gifts of their brains to these projects. All subjects gave informed consent. The Mayo Clinic samples are part of the RNAseq study data led by Dr. Nil{\"u}fer Ertekin‐Taner, Mayo Clinic, Jacksonville, FL as part of the multi‐PI U01 AG046139 (MPIs Golde, Ertekin‐Taner, Younkin, Price). Samples were provided from the following sources: The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. RB thanks her colleagues from the Krumsiek lab for fruitful discussions and support in this work. 2 Funding Information: This work was done as part of the National Institute on Aging's Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP-AD) and was supported by NIH grants 1U19AG063744, 1R01AG069901-01A1, U01AG061357, P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356, RF1AG058942, RF1AG059093, and U01AG061359. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). The Religious Orders and the Rush Memory and Aging studies were supported by the National Institute on Aging grants P30AG10161, R01AG15819, R01AG17917, U01AG46152, and U01AG61356. The NIA also supported the Alzheimer Disease Metabolomics Consortium, which is a part of the NIA's national initiatives AMP-AD and M2OVE-AD (R01 AG046171, RF1 AG051550, and 3U01 AG061359-02S1). We thank the participants of ROS and MAP for their essential contributions and the gifts of their brains to these projects. All subjects gave informed consent. The Mayo Clinic samples are part of the RNAseq study data led by Dr. Nil{\"u}fer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Samples were provided from the following sources: The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. RB thanks her colleagues from the Krumsiek lab for fruitful discussions and support in this work. Publisher Copyright: {\textcopyright} 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
year = "2023",
month = mar,
doi = "10.1002/alz.12714",
language = "English (US)",
volume = "19",
pages = "980--998",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "3",
}