Serum bile acids associated with brain hypometabolism in patients across the Alzheimer's disease continuum

Ali Shushtari; Kosar Shekari; Sina Rashti Mohammad; Sima Alizadeh; Mohammad Allahverdloo; Mohammad Sadeghi; Zahra Zargari; Vida Honarbakhsh Haghighi; Fatemeh Kadaei; Zohreh Zarif; Fatemeh Salimi Eranji; Farhang Ghahrieh; Mahan Shafie; Mahsa Mayeli; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium

doi:10.1016/j.neuroscience.2025.11.001

Serum bile acids associated with brain hypometabolism in patients across the Alzheimer's disease continuum

Neuroscience. 2025 Nov 6:591:177-185. doi: 10.1016/j.neuroscience.2025.11.001. Online ahead of print.

Authors

Ali Shushtari¹, Kosar Shekari², Sina Rashti Mohammad³, Sima Alizadeh⁴, Mohammad Allahverdloo⁵, Mohammad Sadeghi⁶, Zahra Zargari⁷, Vida Honarbakhsh Haghighi⁸, Fatemeh Kadaei⁹, Zohreh Zarif¹⁰, Fatemeh Salimi Eranji¹¹, Farhang Ghahrieh¹², Mahan Shafie¹³, Mahsa Mayeli¹⁴; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium

Affiliations

¹ Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: a.shushtari@mazums.ac.ir.
² Department of Obstetrics and Gynecology, Zhongnan Hospital, Wuhan University, China. Electronic address: Kosarshekari94@gmail.com.
³ Department of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran. Electronic address: S.rashtimohammad@bpums.ac.ir.
⁴ Department of Psychology and Educational Sciences, Semnan University, Semnan, Iran. Electronic address: simaalizadeh90@gmail.com.
⁵ Department of Psychology, Faculty of Literature, Humanities, and Social Sciences, Zanjan Branch of Islamic Azad University, Zanjan, Iran. Electronic address: mohammadalahverdlo@gmail.com.
⁶ School of Rehabilitation, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: sadeghimohammad009@gmail.com.
⁷ Department of Medical Laboratory Sciences, School of Paramedicine, Zanjan University of Medical Sciences, Zanjan, Iran. Electronic address: zahrazargari7813@gmail.com.
⁸ Department of Biochemistry, Tehran Branch of Islamic Azad University, Tehran, Iran. Electronic address: Vida_honarbakhsh@yahoo.com.
⁹ Department of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran. Electronic address: F.kadaei@bpums.ac.ir.
¹⁰ Department of Psychology and Educational Sciences, Shiraz Branch of Islamic Azad University, Shiraz, Iran. Electronic address: Zohrehzarif98@gmail.com.
¹¹ Faculty of Medicine, Tehran Branch of Islamic Azad University, Tehran, Iran. Electronic address: dr.salimi1375@gmail.com.
¹² Student's Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: ghaahrieh@gmail.com.
¹³ School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: M-Shafie@alumnus.tums.ac.ir.
¹⁴ School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: M-Mayeli@alumnus.tums.ac.ir.

PMID: 41205899
DOI: 10.1016/j.neuroscience.2025.11.001

Abstract

The present study compares the predictive performance of serum bile acids with that of conventional Cerebrospinal Fluid (CSF) biomarkers of brain hypometabolism in the Alzheimer's disease (AD) continuum using [¹⁸F]-Fluorodeoxyglucose Positron Emission Tomography ([¹⁸F]-FDG-PET). Data were extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CSF biomarker data, serum bile acid measurements, and [¹⁸F]-FDG-PET data were used. We studied 556 participants, including 185 cognitively normal (CN) individuals, 289 patients with mild cognitive impairment (MCI), and 82 patients with AD. Serum levels of Lithocholic acid and Glycolithocholic acid were significantly elevated in AD compared to MCI and CN participants. Overall, CSF biomarkers had lower predictive power compared to brain hypometabolism in distinguishing AD from other groups. Stronger correlations with brain glucose hypometabolism were observed for conventional CSF biomarkers compared to bile acids in MCI and AD patients. Regression analyses indicated that while certain bile acids predicted brain hypometabolism in CN subjects better than conventional biomarkers, their predictive performance underperformed CSF biomarkers in MCI and AD. Overall, FDG-PET remains more effective than conventional CSF biomarkers for staging the AD continuum. While bile acids show potential, their ability to predict brain glucose metabolism in the AD continuum has not yet surpassed that of established CSF biomarkers.

Keywords: Alzheimer’s disease; Bile acids; Fluorodeoxyglucose; Positron Emission Tomography.