Bile acids in the brain provide a potential treatment target for Alzheimer’s disease

2021

Challenge

Efforts to identify effective drugs to treat Alzheimer’s disease and related forms of dementia, collectively referred to as AD/ADRD, have so far achieved little success. As a result, there is a pressing need to identify novel drug targets that may prove more effective. Past research has suggested that cholesterol and the bile acids that develop as it breaks down may play a role in AD/ADRD, but the precise nature of that relationship has remained a mystery.

Advance

IRP researchers led by Madhav Thambisetty, M.D., Ph.D., analyzed data collected through several large-scale, long-term studies of AD/ADRD and found that lower levels of bile acids in the blood, as well as lower levels of a molecule that serves as a precursor to their formation, are associated with greater accumulation of the beta-amyloid plaques in the brain that are thought to be related to Alzheimer’s disease. Lower levels of those molecules were also associated with faster brain atrophy during aging and more rapidly progressing damage to the brain’s white matter, especially in men. Moreover, men who had taken a type of cholesterol-lowering medication that affects bile acid levels had a higher risk of a form of dementia called vascular dementia. Finally, the researchers reviewed brain tissue from deceased Alzheimer’s patients and found altered levels of many bile acid receptors.

Impact

These findings provide evidence that bile acids may influence risk for AD/ADRD by altering signaling pathways in the brain through their receptors. These abnormalities in bile acid signaling may be an important treatment target for AD/ADRD.

Publications

Varma Vr, Wang Y, An Y, Varma S, Bilgel M, Doshi J, Legido-Quigley C, Delgado JC, Oommen AM, Roberts JA, Wong DF, Davatzikos C, Resnick SM, Troncoso JC, Pletnikova O, O’Brien R, Hak E, Baak BN, Pfeiffer R, Baloni P, Mohmoudiandehkordi S, Nho K, Kaddurah-Daouk R, Bennett DA, Gadalla SM, Thamisetty M. (2021). Bile acid synthesis, modulation and dementia: a metabolomic, transcriptomic and pharmacoepidemiologic study. PLoS Med. May 27;18(5):e1003615. doi: 10.1371/journal.pmed.1003615.