Of all of our organs, our brains and hearts get the most attention. But the liver once held top billing, preeminent over the heart and mind as the seat of emotion and even the soul. As its name implies, we need our liver to live—not only because it works hard as a detox unit but also because it quietly processes components our brains need to thrive.

The Alzheimer’s disease (AD) research community is turning its attention to this liver–brain connection. That newfound interest turns up in a quartet of new studies presented July 24 at the Alzheimer’s Association International Conference 2018. The results may help provide clues to both the basic biology of AD and how diet is linked to brain health. More specifically, it may give insight into why human clinical trials of fish oil have failed to protect against AD and other forms of dementia.

In the four studies, blood levels of molecules associated with the liver and production of fats, or lipids, were tied to AD risk—a first step toward deeper examination of the liver–brain link. “There seem to be some positive results correlating levels of lipids with cognition and cognitive progression,” says Paul Schulz, director of the Dementia and Memory Disorders Clinic at The University of Texas McGovern Medical School, who was not involved in the studies. “The challenge will be to establish cause and effect.”

The brain consists mostly of fats, which contribute to both its form and function. These lipids facilitate communication from neuron to neuron and make up much of the insulation that sheaths these cells. It is the liver that builds the fats the brain needs—and many genes tied to AD are linked to fat production or transport, including a version of a gene associated with high AD risk—APOE ε4.

The brain needs omega-3 fatty acids, which we obtain from our diets. But the omega-3 sources we consume cannot be delivered as is to the brain. The microbes in our gut, known as the microbiome, contribute to lipid processing. In the final steps the liver creates brain-specific fats inside cell structures called peroxisomes. Once these fats are synthesized, the blood transports them to the brain, where they form cell structures and also help neurons communicate.

Recognizing the central role of the liver in the brain’s health, the four research groups measured blood levels of these brain-critical lipids and the molecules that make them. Three of the four non–peer-reviewed investigations presented at the Alzheimer’s meeting relied on information from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a project in its 13th year of collecting imaging, genetic, blood and other data on thousands of people—both healthy and those with cognitive impairment, including AD patients. The remaining study used data from a Dutch population.

One group, from the Alzheimer’s Disease Metabolomics Consortium, looked at lipids called plasmalogens, fats that contain the omega-3 fatty acids DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid). They found reduced blood levels of these fats tracked with increased AD risk among ADNI participants. A second group also working with information from ADNI found similar hints of lipid-processing anomalies in blood samples. In the latter study even people with AD who took fish oil supplements did not have increased blood levels of brain-beneficial lipids, possibly pointing to why fish oil supplementation does not appear to stem cognitive decline.

If peroxisomes in the liver are not working properly, “taking more fish oil won’t let you make more plasmalogens because the machinery for making them is defective,” says Mitchel Kling, associate professor of psychiatry at the University of Pennsylvania Perelman School of Medicine, whose group focused on plasmalogens.

In fact, fish oil supplementation might be a bit of a double-edged sword, says Dinesh Kumar Barupal, project scientist and program coordinator for the West Coast Metabolomics Center at the University of California, Davis, whose group looked at fish oil supplementation in the ADNI cohort. “We found that taking fish oil can increase levels of some lipids but can also decrease levels of other lipids.” Fish oil, in fact, was associated with reduced blood levels of a kind of omega-3 from plants that’s an important brain fat, he says.

Other explanations are possible as well: “There is some recent suggestion that patients with APOE ε4 have altered DHA metabolism,” says Howard Fillit, founding executive director and chief science officer at the Alzheimer's Drug Discovery Foundation, who was not involved in the studies. Another possibility, he says, is that eating habits might change as dementia progresses. Schulz agrees changes in diet could underlie the association. “AD patients often lose their sense of taste and smell, and then their diet changes from healthy items to sweet and fatty items that they can still taste,” he says. “It becomes challenging to know whether what we are seeing now is a cause or an effect.

Breaking down fats in fish oil or the rest of the diet requires bile acids, which the liver produces from cholesterol, and the microbial denizens of the gut produce in the colon. Because bile acids represent another important step in making fats, investigators on the two other studies honed in on these factors. In the work involving the Dutch group, Shahzad Ahmad, a doctoral student at Erasmus University Medical Center in Rotterdam, and colleagues found links between AD-related gene variants and bile acid levels, which suggests genes may interact with the microbiome in the development of AD.

In the final study Kwangsik Nho, assistant professor of radiology at the Center for Neuroimaging at the Indiana University School of Medicine, and colleagues also used ADNI information and found an association of high levels of microbiome-related bile acids with AD-related findings on brain imaging. They also found ties between low levels of liver-based bile acids and signs of memory deficits.

Together, these four studies seem to draw a dotted line from the gut microbiome to the liver to the brain. But right now what lies from point to point is a black box. “There is a lot that we don’t know in between those things,” says James Hendrix, director of Global Science Initiatives for the Alzheimer’s Association, which contributes funding to the consortia of groups conducting this research. That means the world is years away from clinical applications related to such findings, he says.

Duke University professor of psychiatry and behavioral sciences Rima Kaddurah-Daouk, who leads the Metabolomics Consortium, which conducted some of the research, says these results indicate the need to look outside the brain to explain the brain. Pointing to a host of unsuccessful AD-related clinical trials based on data only from brain studies, she adds, “studying the brain alone is no more an option.”