New Potential Link Between Alcoholism, Fatty Liver Disease, and Alzheimer’s Disease Identified by Dr. Derick Han’s Team

Keck Graduate Institute Associate Professor of Biopharmaceutical Sciences Dr. Derick Han—along with Dr. Rachita Sumbria (formerly of KGI, now at Chapman), University of La Verne Professor Dr. Jerome Garcia, and several KGI students—recently published a new article potentially linking alcoholic liver disease and Alzheimer’s disease (AD). Heavy alcohol consumption is a known risk factor for various forms of dementia and AD development, but the mechanism is not entirely understood.

The article, “Modulation of hepatic amyloid precursor protein and lipoprotein receptor-related protein 1 by chronic alcohol intake: Potential link between liver steatosis and amyloid-β,” published September 15 in Frontiers in Physiology, suggests that liver damage caused by alcohol changes critical proteins in the liver that may promote AD.

Though AD and related forms of dementia currently impact an estimated 5.8 million people in America, understanding how the disease develops remains incomplete, and even less is known about its link to alcoholism. Most existing studies tend to focus on the effect of alcohol on the brain and have not generally explored the role of the liver.

Han has long studied the impact of metabolic stress on liver mitochondria, the organelles known as the cell’s powerhouse. Early findings from his research were surprising. While most studies published since the 1980s have found alcohol to have a negative effect on liver mitochondria, he discovered that mitochondria improve their ability to adapt to the stress of alcohol intake on the liver in the short term.

In the fall of 2019, Han and Sumbria received a five-year grant from the National Institutes of Health (NIH) to investigate the role of alcohol-induced liver damage in the progression of AD.

“Alcohol consumption affects all tissues at some level, but the liver is one of the most heavily impacted organs because it’s where alcohol is metabolized,” Han said.

While alcohol has many effects on the brain, chronic alcohol consumption most directly damages the liver, which manifests as alcoholic steatosis (fatty liver disease), hepatitis (inflammation plus fatty liver), and cirrhosis (fibrosis due to significant death of hepatocytes—cells that play pivotal roles in metabolism, detoxification, and protein synthesis.)

The liver performs many essential functions for brain health, including regulating amyloid-beta (Aβ). This protein can aggregate and form the brain’s plaques associated with AD.

“In our study, we found that when you give alcohol to mice, two important proteins that regulate Aβ in the liver become misregulated,” Han said. “One is the amyloid precursor protein (APP), which gets cleaved and becomes Aβ. We see it increasing around 100%, or in some cases, 200%. So we think the liver starts making more of this protein, which leads to more Aβ.”

That Aβ made in the liver can eventually cross the blood-brain barrier to promote AD. Additionally, they found that alcohol consumption downregulated lipoprotein receptor-related protein 1 (LRP1), the major receptor in the liver that removes Aβ from blood and peripheral organs, by 46%.

Thus, the simultaneous decrease in LRP1 and increase in APP likely switches the liver’s role from being a remover or low producer of Aβ to an essential source of Aβ, which can impact the brain.

“One thing that differentiates our study is that we used different models to compare levels of consumption—binge drinking versus more steady consumption throughout the day,” said KGI student Ross Steinberg, PhD ’24, who co-authored the publication and performed much of the gene analysis.

Though they found a significant difference between the effects of heavy and moderate alcohol consumption on the misregulation of LRP1 and APP, even moderate consumption had an impact.

Additionally, they found obesity, which also causes fatty liver disease (non-alcoholic steatosis), similarly affects APP and LRP1 in the liver of obese mice. Obesity, especially in midlife, is also a risk factor for AD. Therefore, fatty liver may be the uniting factor in changing LRP1 and APP levels in the liver to promote AD.

While additional research could potentially lead to gene therapies, lifestyle modification is currently the best way to prevent fatty liver disease—and by extension, guard against AD.

“At this point, we can see a promising link between fatty liver disease and Alzheimer’s, but we need further experiments to determine if it is an absolute causal relationship,” Han said.

They plan to conduct experiments where they’ll modulate these genes in the liver to determine how—and to what extent—misregulation of APP and LRP in the liver contributes to AD.

“Working on these cross-institution, collaborative experiments were a great opportunity, and it was exciting to see everything come together,” Steinberg said. “I got to work with some really bright collaborators and learn many new techniques. It broadened my horizons regarding how I think about the research.”