Rethinking on bile acid-brain axis: decoding neurotoxic and neuroprotective landscape in aging and Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aging serves as the predominant risk factor. Emerging research underscores the importance of bile acids (BAs), traditionally recognized for their role in digestion, as key signaling mediators involved in both systemic metabolism and neural communication. Disruption of bile acid (BA) metabolism during aging arises from altered hepatic synthesis, gut microbial imbalance, and defective receptor signaling. These changes have been implicated in several neurodegenerative processes, including Aβ accumulation, tau protein abnormalities, mitochondrial impairment, and disturbances in immune regulation. Aging induces a shift in BA composition toward more cytotoxic species, contributing to blood-brain barrier disruption and enhanced neuronal damage. Multi-omics analyses have identified distinct BA signatures in plasma and cerebrospinal fluid of individuals with mild cognitive impairment and AD. These alterations show strong correlations with brain atrophy and progressive cognitive decline. Experimental and early clinical findings suggest potential neuroprotective effects of hydrophilic BAs such as ursodeoxycholic acid and tauroursodeoxycholic acid, along with therapeutic opportunities through modulation of BA receptors and microbiome-driven BA regulation. In the current era of AD research, the gut-liver-brain BA axis emerges as a novel mechanistic framework linking systemic metabolic aging to neurodegeneration. This review examines the molecular pathways through which BA dysregulation influences aging and AD, emphasizing its therapeutic relevance and supporting the development of biomarker-based and precision medicine approaches for neurodegenerative disorders.