Genetic variants linked to Alzheimer’s trigger brain inflammation in women, preclinical study finds

Weill Cornell Medicine researchers have discovered that two genetic variants that confer high risk of Alzheimer’s disease (AD) together trigger a harmful inflammatory response in immune cells in the brain, particularly in women, in a preclinical model.

The results, published on September 30 in Neuronhighlight the importance of considering gender differences in Alzheimer’s research, a step that could eventually lead to more precise and effective treatments.

Alzheimer’s disease affects millions of people worldwide, and women are disproportionately affected: nearly twice as many women as men develop the disease. To advance therapeutic approaches, researchers are trying to determine the basis of these differences in vulnerability.

Previous studies have shown that a gene variant called APOE4 increases the risk of AD more in women than in men. The current study focused on the cellular activities that go awry when APOE4 and a TREM2 gene variant, which also increases AD risk, are present together in women. Because the proteins encoded by these genes serve diverse functions in cells, it is not clear how these particular variants contribute to disease vulnerability.

“Although these are two of the most important risk factors for Alzheimer’s disease, little is known about how they increase disease risk and they have not often been studied together” , said lead author Dr. Li Gan, director of Helen and Robert Appel’s Alzheimer’s disease research. Institute and Burton P. and Judith B. Resnick Distinguished Professor of Neurodegenerative Diseases at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. “Our goal was to combine these risk factors to highlight which pathways are altered when disease risk is greatest.”

Dr. Gan and his team, including lead author Dr. Gillian Carling, a graduate student at the Weill Cornell Medicine Graduate School of Medical Sciences at the time of the study, established mouse models for AD carrying human versions of APOE4 and TREM2 R47H, a rare variant that increases the risk of AD by 2 to 4.5 times.

The mice also carried a mutation leading to the development of tau protein clumps, which are abundant in AD brains and closely associated with patients’ cognitive decline. The team examined the mice at 9 to 10 months of age, roughly the average age in humans, to assess the impact of these genetic variants on brain health.

They found that female, but not male, mice with both APOE4 and TREM2 R47H had significant damage to the region of the brain that plays an important role in thinking and memory. This damage included clumps of tau proteins that were more severe than those in mice lacking these gene combinations.

Researchers attributed the damage to these women’s brains to the brain’s immune cells, called microglia. Normally, microglia protect the brain, but in this case they have become “senescent,” referring to aged cells that have lost their ability to function properly. Instead of clearing out damaged cells and protein clumps, these aged microglia persist and release inflammatory chemicals through a pathway known as cGAS-STING.

Notably, the study found that these harmful effects were more pronounced in female mice, a finding consistent with reports that APOE4 poses a higher risk to women than men.

“Our research has shown that when both Alzheimer’s risk factors are combined in women with tau aggregates, the cGAS-STING pathway becomes highly activated,” Dr. Carling said. Suppression of this deleterious pathway reduced harmful inflammatory factors and rescued the aging phenotype of microglia.

The study highlights the need to consider gender differences in Alzheimer’s disease research and treatment, researchers say, because the disease may progress differently in men and women and may therefore require different approaches. adapted, commented Dr Gan.

By identifying the role of immune pathways like cGAS-STING in the progression of Alzheimer’s disease, particularly in people with high-risk genetic variants, researchers hope to open the door to new treatment and potentially prevention strategies. .