Alcohol Use Disorder Harms the Brain’s Immune System Earlier in Women

The immune system is the body’s protector. Following the detection of a potential threat, such as a bacterial or viral infection, a healthy immune system will attack the foreign invader. What many people don’t realize is that our brains have their own unique immune system, made up of cells called microglia that play an essential role in maintaining brain function.

Previous research has demonstrated that alcohol consumption signals a potential threat to the brain’s immune system and activates microglia to initiate repair functions. Now, a new study in Biological Psychiatry, led by researchers at the Yale-SCORE Program for Sex Differences in Alcohol Use Disorder, reveals a surprising finding: Women with alcohol use disorder have lower levels of microglia than healthy women. This is not the case for men.

Alcohol use disorder is on the rise in women. This trend is especially concerning because women who drink are at a disproportionately greater risk for brain damage, cognitive deficits, and a range of other adverse effects when consuming lower amounts of alcohol compared to their male counterparts.

The researchers behind the new study believe that in women, the constant activation of microglia due to excess drinking might be exhausting the immune cells and depleting them. This, in turn, could lead to decreased immune system function, and it might help explain why women are especially vulnerable to alcohol-related health risks.

“A couple of drinks will wake up the microglia to see if there’s a problem,” says Kelly Cosgrove, PhD, professor of psychiatry at Yale School of Medicine (YSM) and senior author of the study. “But if you do that every day over years, or over decades, they eventually give up. And then you can start to see cognitive decline.”

The researchers, led by Yasmin Zakiniaeiz, PhD, assistant professor of psychiatry at YSM, enrolled both men and women primarily with mild or moderate alcohol use disorder, as well as healthy controls. All of the participants underwent a positron emission tomography scan to image microglia in the brain, answered questionnaires about their mood and anxiety, and took a test measuring cognitive function.

The study found that healthy women have higher levels of microglia compared to healthy men. Because women are at a greater risk for autoimmune disorders, it was not surprising to Cosgrove that the brain’s immune system in women might also be more active. “The healthy brains of women have higher levels of microglia, and that may or may not go along with the fact that women do have an increased propensity to immune-related disorders,” she says.

Among individuals with alcohol use disorder, the team found a microglial deficit in women compared to their healthy counterparts, but not in men. Previous research on primarily male cohorts with more severe alcohol use disorder, however, has shown this deficit. The current study suggests that women might start losing their microglia at earlier stages, says Cosgrove, who is also a professor of neuroscience and of radiology and biomedical imaging.

This deficit in the brain’s immune system could have significant health impacts. Based on the questionnaires of study participants with alcohol use disorder, the researchers found that women, but not men, had worsened mood and higher levels of anxiety.

Women with alcohol use disorder also had lower levels of executive functioning, which refers to the cognitive skills we use to complete everyday tasks such as planning or problem solving. The researchers found that lower levels of microglia in a brain region known as the cerebellum, in particular, were associated with worse executive function. The cerebellum plays a vital role in motor function, but also is involved in cognitive and emotional functions.

“This is a glimmer into how immune system dysfunction is associated with cognitive function,” Cosgrove says. “If you don’t have a healthy brain immune system, then other parts downstream will start to break down as well.”

Today, most available treatments for alcohol use disorder were developed based on research involving primarily men. The new study could help inform the development of novel therapeutics designed for women that target the brain’s immune system.

Cosgrove adds that the study is evidence that improving other factors known to boost immune processes—such as sleep, exercise, and healthy diet—may also help women in their recovery. While researchers still don’t know if the microglial deficit is permanent, Cosgrove says the human brain’s resilience makes her optimistic.

“You can’t solely focus on giving someone a medication to tweak their brain chemistry,” she says. “Clinicians need to take a more holistic approach.”

The research reported in this news article was supported by the National Institutes of Health (awards U54AA027989 [Yale-SCORE ORWH/NIAAA], MH110674, P01AA02747307, K01AA029706, and K24AA031345) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.