Gut inflammation associated with age and Alzheimer’s disease pathology

Age-related disease may be mediated by low levels of chronic inflammation (“inflammaging”). Recent work suggests that gut microbes may contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer’s disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation and permeability per se remains unclear. To test whether greater gut inflammation is associated with older age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Here we found that calprotectin levels are higher with age, and that higher calprotectin was associated with greater amyloid burden among participants with an amyloid-confirmed AD dementia diagnosis. Calprotectin was also associated with cerebrospinal fluid markers of AD pathology and axonal degeneration, as well as with lower verbal memory function among cognitively unimpaired participants. Together, these findings suggest that intestinal inflammation may play a role in pathology development, and that it may exacerbate the progression toward AD. Summary Intestinal inflammation is correlated with older age, Alzheimer’s disease (AD) dementia, and greater amyloid burden in participants with AD. ### Competing Interest Statement Roche Diagnostics International Ltd (Rotkreuz, Switzerland) provided CSF testing equipment and analysis for Drs. Bendlin and Johnson. COBAS, COBAS E, and ELECSYS are trademarks of Roche. The Roche NeuroToolKit is a panel of exploratory prototype assays designed to robustly evaluate biomarkers associated with key pathologic events characteristic of AD and other neurological disorders. It is used for research purposes only and is not approved for clinical use. GK is a full-time employee of Roche Diagnostics GmbH. IS is a full-time employee of Roche Diagnostics International Ltd. NW is a full-time employee of Roche Diagnostics GmbH. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. GK is a full-time employee of Roche Diagnostics GmbH (Penzberg, Germany). IS is a full-time employee and shareholder of Roche Diagnostics International Ltd (Rotkreuz, Switzerland). BBB has received precursor and imaging agents from AVID radiopharmaceuticals. ### Funding Statement Wisconsin Partnership Program grant (BBB, FER) Geriatric Research, Education, and Clinical Center of William S. Middleton Memorial Veterans Hospital (BBB, SCJ) National Institute on Aging grant R01AG070973 (BBB, FER, TKU) National Institute on Aging grant R01AG070883 National Institute on Aging grant R01AG037639 National Institute on Aging grant R01AG054059 National Institute on Aging grant P30AG062715 (SCJ) National Institute on Aging grant R01AG021155 (SCJ) National Institute on Aging grant R01AG27161 (SCJ) National Institute of Child Health and Human Development grant U54HD090256 National Institute of General Medical Sciences grant T32GM081061 (MBH) Clinical and Translational Science Award grant UL1TR000427 Swedish Research Council grant 2018-02532 (HZ) European Research Council grant 681712 (HZ) European Research Council grant 101053962 (HZ) Swedish State Support for Clinical Research grant ALFGBG-71320 (HZ) Swedish State Support for Clinical Research grant ALFGBG-720931 (HZ) Alzheimer Drug Discovery Foundation grant 201809-2016862 (HZ) AD Strategic Fund and Alzheimer's Association grant ADSF-21-831376-C (HZ) AD Strategic Fund and Alzheimer's Association grant ADSF-21-831381-C (HZ) AD Strategic Fund and Alzheimer's Association grant ADSF-21-831377-C (HZ) Olav Thon Foundation (HZ) Erling-Persson Family Foundation (HZ) Stiftelsen for Gamla Tjanarinnor grant FO2019-0228 (HZ) European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (HZ) UK Dementia Research Institute at University College London (HZ) Swedish Research Council grant 2017-00915 (KB) Alzheimer Drug Discovery Foundation grant RDAPB-201809-2016615 (KB) Swedish Alzheimer Foundation AF-742881 (KB) Hjarnfonden, Sweden grant FO2017-0243 (KB) Swedish State Support for Clinical Research grant ALFGBG-715986 (KB) European Union Joint Program for Neurodegenerative Disorders grant JPND2019-466-236 (KB) National Institute of Health grant R01AG068398 (KB) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of University of Wisconsin-Madison gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes 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). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data collected via the Wisconsin ADRC and WRAP protocols may be requested via an online REDCap request tool, which can be accessed at https://www.adrc.wisc.edu/apply-resources.