INTRODUCTION Mounting evidence support exposome influences on brain function and health, complementing genome influences. Understanding the molecular imprint of exposome on brain metabolism and the biochemical communication between the body and brain can impact our fundamental understanding and treatment of neuropsychiatric diseases.

METHODS Leveraging two complementary metabolomics platforms, we classified 1400 features in 514 brains from the ROSMAP collection. We evaluated the origin of these compounds using literature and databases. We correlated those metabolites with cognitive function using linear models.

RESULTS We identified over 230 non-endogenous compounds in the brain, including 103 drugs and metabolites, 120 dietary and microbial products and possibly 15 compounds from environmental exposures. Over 20 dietary and gut microbial compounds showed associations with cognition.

DISCUSSION Comprehensive profiling of chemicals in the brain and the link to cognitive function provides foundational work to connect body and brain in the study of AD and related dementias.

P.C.D. is an advisor and holds equity in Cybele, BileOmix, and Sirenas, and a Scientific co-founder, advisor, holds equity and/or received income to Ometa, Enveda, and Arome with prior approval by UC-San Diego. P.C.D. also consulted for DSM animal health in 2023. Dr. Kaddurah-Daouk is an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia and Metabosensor.

The Alzheimer’s Gut Microbiome Project (AGMP) and the Alzheimer’s Disease Metabolomics Consortium (ADMC) are funded wholly or in part by the following grants and supplements awarded to Dr. Kaddurah-Daouk at Duke University in partnership with a large number of academic institutions: R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, U19AG063744, 3U19AG063744-04S1, RF1AG058942, 1U01AG088562, U01AG061359, R01AG081322, FNIH: #DAOU16AMPA and FNIH: AMP AD 2.0 (AMP AD 2.0 is a public-private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute on Aging (NIA) in partnership with the private sector. For up-to-date information on the partners, visit https://fnih.org/our-programs/accelerating-medicines-partnership-amp/amp-alzheimers-disease-2-0/). As such, the investigators within the AGMP and the ADMC, not listed specifically in this publication’s author’s list, provided analysis-ready data, but did not participate in designing the study, conducting the analyses or writing of this manuscript. A listing of AGMP Investigators can be found at https://alzheimergut.org/meet-the-team/. A listing of ADMC investigators can be found at: https://sites.duke.edu/adnimetab/team/. Lurian Caetano David is supported by the Fulbright U.S. Student Program through the DDRA (Doctoral Dissertation Research Award), which is sponsored by the U.S. Department of State and the Fulbright Brazil Commission.

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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 Study (ROS) and the Rush Memory and Aging Project (MAP) are two ongoing longitudinal clinicopathologic cohorts established by the Rush Alzheimer’s Disease Center. ROS was initiated in 1994 with participants recruited from religious communities across the United States. MAP began in 1997 and enrolled individuals from diverse educational and socioeconomic backgrounds in northeastern Illinois. Both studies were approved by the Institutional Review Board of Rush University Medical Center.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org)

https://adknowledgeportal.org