Bile acids play a key role in Alzheimer’s disease

Bile acids, long known for their role in fat digestion and liver metabolism, also influence the central nervous system. They act as signaling molecules capable of modulating brain homeostasis via a liver-gut-brain axis. These compounds, produced by the liver from cholesterol, are transformed by gut bacteria into secondary bile acids and then largely recycled by the body. A small fraction even reaches the brain, where they can cross the blood-brain barrier depending on their hydrophilic or lipophilic nature.

In Alzheimer’s disease, characterized by the accumulation of beta-amyloid peptides and abnormal tau proteins, bile acid profiles are often disrupted. Studies show a decrease in primary bile acids and an increase in secondary acids, particularly hydrophobic ones such as deoxycholic acid and lithocholic acid. In excess, these promote the breakdown of the blood-brain barrier and neurotoxicity, thereby worsening the symptoms of the disease. Conversely, some hydrophilic bile acids, such as tauroursodeoxycholic acid, exert protective effects by reducing inflammation and limiting the formation of amyloid plaques.

These molecules act directly in the brain by activating specific receptors, such as FXR and TGR5, which regulate neurotransmitter activity and neurobehavioral responses. FXR, for example, inhibits the production of pro-inflammatory cytokines, while TGR5 limits the activation of microglial cells, thereby reducing neuroinflammation. Additionally, bile acids stimulate the release of gut hormones such as GLP-1 and FGF19, which improve insulin sensitivity in the brain and support cognitive functions. GLP-1, in particular, enhances the production of neurotrophic factors, protecting neurons against degeneration.

At the same time, bile acids influence the composition of the gut microbiota. Certain bacteria, such as those in the Clostridium group, convert primary acids into potentially neurotoxic secondary acids. An imbalance in this flora, called dysbiosis, can therefore worsen the mechanisms of Alzheimer’s disease by promoting the accumulation of harmful metabolites. The vagus nerve, which connects the gut to the brain, also plays a key role by transmitting signals related to these metabolites, contributing to the regulation of inflammation and cognition.

Finally, hydrophilic bile acids, such as ursodeoxycholic acid, have demonstrated neuroprotective properties in preclinical models, reducing brain damage and preserving memory functions. Their therapeutic potential, although promising, still requires in-depth clinical trials to confirm their effectiveness in humans. Thus, bile acids represent an innovative avenue for understanding and treating Alzheimer’s disease, targeting both the central and peripheral mechanisms of this complex pathology.

Information and Sources

Scientific Reference

DOI: https://doi.org/10.1007/s00210-026-05516-1

Title: Bile acids in Alzheimer’s disease: a double-edged sword in gut–liver–brain signaling and neurodegeneration

Journal: Naunyn-Schmiedeberg’s Archives of Pharmacology

Publisher: Springer Science and Business Media LLC

Authors: Rehana Basri; Hayder M. Al-kuraishy; Mubarak Alruwaili; Ali I. Al-Gareeb; Ali K. Albuhadily; Athanasios Alexiou; Marios Papadakis; Safaa A. Faheem; Gaber El-Saber Batiha