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CHICAGO -- Converging research about the gut-liver-brain axis showed connections between the digestive system and markers of Alzheimer's disease, though questions of correlation versus causality remain.

Four studies reported at the suggested gut and liver functions may be related to changes in the brain. One showed microbiome-produced bile acid profiles may be altered in people with Alzheimer's disease, for example; another showed liver-created lipids vital to cell membranes may be reduced in Alzheimer's patients.

The studies all were conducted for the (ADMC), part of the National Institute on Aging (NIA) (AMP-AD).

"We have studied the brain in isolation for too long," said consortium leader Rima Kaddurah-Daouk, PhD, of Duke University. "Not only should we be targeting the brain; we should be targeting other organs that talk to the brain."

In what may be the first study linking bile acid profiles with Alzheimer's disease biomarkers, Kwangsik Nho, PhD, of the Indiana University School of Medicine in Indianapolis, and colleagues, reported that people with Alzheimer's disease had increased gut microbiome-produced bile acids, which were associated with changes in cognitive decline, reduced brain glucose metabolism, and greater brain atrophy.

These same bile acids were linked to increased amyloid and tau accumulation, said Nho and co-authors in an analysis of 1,562 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

In the second consortium study, Mitchel Kling, MD, of the University of Pennsylvania, and co-authors reported that among ADNI participants and Penn Memory Center patients, reduced levels of plasmalogens -- a class of lipids that help facilitate synaptic function -- were tied to an increased risk of cognitive impairment.

"The failure of the liver to provide sufficient plasmalogens to the brain could contribute to reduced ability of neurons to release neurotransmitters and thus communicate with other neurons," Kling told MedPage Today.

Low plasmalogen indices were correlated with elevated cerebrospinal fluid (CSF) levels of total tau but not with amyloid-beta, suggesting that low plasmalogen availability to the brain may be something that occurs during the prodromal phase of Alzheimer's disease, he said.

"Some of our results provide a possible explanation for the mixed results observed in trials of omega-3 fatty acid-containing products, such as fish oils, to prevent cognitive decline in older individuals," Kling added. "One of the indices we measured, based on the ratios of omega-3 fatty acid-containing plasmalogens to the corresponding phosphatide, was not affected by whether or not subjects were taking fish oils in our study, indicating that intake of omega-3 fatty acids cannot by itself drive plasmalogen production if the enzymatic machinery in the liver is not functioning normally."

The third consortium study, led by Dinesh Kumar Barupal, PhD, of the University of California Davis, sought to identify lipid biomarkers for Alzheimer's and saw that fish oil intake failed to bring key lipid levels back to normal in Alzheimer's patients: "While levels of eicosapentaenoic acid- and docosahexaenoic-containing phospholipids increased with fish oil products, levels of arachidonic acid-containing phospholipids went down," Barupal said.

And in the fourth analysis from the consortium, Shahzad Ahmad, MSc, of the Erasmus Medical Center in Rotterdam, and colleagues found that variations in Alzheimer's risk genes APOE4 and SORL1 in two Dutch cohorts were tied to decreased levels of several cholesterol components that may be important for brain cell membrane health.

These studies all indicate something is altered in the gut and liver of Alzheimer's patients, Kaddurah-Daouk observed, but whether the changes are cause or effect is unknown.

"We can point now to problems in the gut and problems in the liver that are communicating with some aspects of disease in the brain in Alzheimer's, suggesting we really should pay more attention to the interconnectedness of the brain with other organs," she said.

"Maybe we can come up with drugs that can target the liver. Maybe we can repurpose drugs that are being used for liver diseases, or use drugs that target the gut and bacteria."