Serum bile acids improve prediction of Alzheimer’s progression in a sex-dependent manner

INTRODUCTION There is evidence that there are differences in the serum levels of bile acids (BAs) in males and females and their risk of developing Alzheimer’s disease (AD). We previously reported that serum BAs are associated with AD. It remains unclear, however, how changes in serum BAs may relate to the development of AD in a sex-dependent manner. METHODS We analyzed 33 BAs in the sera of 4219 samples from 1180 subjects in the ADNI cohort. Using linear models, we examined the associations between BAs and mild cognitive impairment (MCI) progression and clinical markers. RESULTS Significant alterations in BA profiles occurred at an early stage of MCI and were associated with the onset and progression of MCI. These changes were more dramatic in men than in women. BA markers improved the ability of current clinical markers to diagnose MCI and predict its progression. DISCUSSION Our results highlight the role of BAs in the development of AD and may help improve AD prediction and personalized therapies. Research in context 1. Systematic review: We examined the relationship between bile acid (BA), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). We previously reported this association. Our findings were consistent with those of other studies, although previous research did not consider sex differences or comprehensively evaluate the potential of BAs as diagnostic markers for AD. 2. Interpretation : Our results suggest that changes in BA profiles may play a role in the development of AD and that sex-specific differences may be important for personalized prediction and management of the disease. 3. Future directions : In the future, it will be important to confirm our findings with other independent samples and further investigate the ways in which BA metabolism, including cholesterol catabolism in the liver and brain, may contribute to AD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by National Key R&D Program of China (2021YFA1301300) and National Natural Science Foundation of China (82270917, 81974073, and 31972935). Funding for ADMC (Alzheimer's Disease Metabolomics Consortium, led by Dr R.K.D. at Duke University) was provided by the National Institute on Aging grant R01AG046171, a component of the Accelerating Medicines Partnership for AD (AMP AD) Target Discovery and Preclinical Validation Project () and the National Institute on Aging grant RF1 AG0151550, a component of the M2OVE-AD Consortium (Molecular Mechanisms of the Vascular Etiology of AD Consortium ). ### 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: Metabolomics datasets used in the current analyses for the ADNI 1 and ADNI GO 2 cohorts are available via the Accelerating Medicines Partnership Alzheimer's Disease (AMP AD) Knowledge Portal and can be accessed at (ADNI 1) and (ADNI GO 2). The full complement of clinical and demographic data for the ADNI cohorts are hosted on the LONI data sharing platform and can be requested at . 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 Metabolomics datasets used in the current analyses for the ADNI 1 and ADNI GO 2 cohorts are available via the Accelerating Medicines Partnership Alzheimer's Disease (AMP AD) Knowledge Portal and can be accessed at (ADNI 1) and (ADNI GO 2). The full complement of clinical and demographic data for the ADNI cohorts are hosted on the LONI data sharing platform and can be requested at . * Abbreviations: NC : Normal cognition MCI : Mild cognitive impairment EMCI : Early mild cognitive impairment LMCI : Late mild cognitive impairment AD : Alzheimer’s disease sMCI : sustained MCI cMCI : converted MCI ADNI : Alzheimer’s Disease Neuroimaging Initiative ROSMAP : Religious Orders Study and Rush Memory and Aging BA : Bile acid TBA : Concentration of total bile acids CA : Cholic acid CA% : Concentration percentage of cholic acid to total bile acids DCA/CA : Ratio of deoxycholic acid and cholic acid GDCA/CA : Ratio of deoxycholic acid glycine conjugate and cholic acid CDCA : Chenodeoxycholic acid A/T/N : Amyloid-beta, tau, and neurodegenerative APOE-4 : apolipoprotein E ε4 genotype UK CPRD : Clinical Practice Research Datalink database of United Kingdom AUC : Area under Receiver Operating Characteristic Curve UPLC-MS/MS : ultra-performance liquid chromatography coupled to tandem mass spectrometry PCA : Principle component analysis LOESS : locally weighted regression