Two genetic variants linked to Alzheimer’s trigger microglial inflammation in females

Researchers at Weill Cornell Medicine have discovered in a preclinical model that two genetic variants that confer a high risk for Alzheimer’s disease (AD) combine to cause a damaging inflammatory response in the brain’s immune cells, especially in women.

The findings, published September 30 in Neuron, highlight the importance of considering sex differences in Alzheimer’s disease research — a step that could ultimately lead to more precise and effective treatments.

AD affects millions of people around the world, with women disproportionately affected; almost twice as many women develop the disease as men. To advance therapeutic approaches, researchers are trying to determine the basis for these differences in vulnerability. Previous studies have shown that a gene variant called APOE4 increases AD risk more in women than in men. The current study focused on cellular activities that go awry when APOE4 and a variant of the TREM2 gene, which also increases AD risk, are present together in women. Because the proteins encoded by these genes have a variety of functions in cells, it is unclear how the specific variants contribute to vulnerability to the disease.

Although these are two of the strongest risk factors for AD, little is known about how they increase disease risk and they have not often been studied together. Our goal was to combine these risk factors to highlight which pathways are altered when the risk of disease is greatest.”

Dr. Li Gan, senior authordirector of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor of Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine

Dr. Gan and her 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, developed mouse models of AD with human versions of APOE4 and TREM2 R47H, a rare variant that increases AD risk 2-4.5 times increases. The mice also carried a mutation that leads to the development of clumps of tau protein – abundant in AD brains and closely linked to cognitive decline in patients. The team examined the mice at 9 to 10 months of age, roughly equivalent to middle age in humans, to assess how these genetic variants affected brain health.

They found that female, but not male, mice with both APOE4 and TREM2 R47H showed significant damage to the brain region that plays an important role in thinking and memory. This damage included more severe tau protein clumps compared to those mice without these gene combinations.

The researchers attributed the damage in these female brains to the brain’s immune cells called microglia. Normally, microglia protect the brain, but in this case they became “senescent,” referring to senescent cells that lost their ability to function properly. Instead of clearing away damaged cells and protein clumps, these old microglia stick around 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 that echoes reports that APOE4 poses a greater risk for women than men.

“Our research showed that when the two risk factors for Alzheimer’s disease in women are combined with tau aggregates, the cGAS-STING pathway is strongly activated,” said Dr. Carling. Suppressing this damaging pathway reduced harmful inflammatory factors and rescued the aging phenotype in microglia.

The study underlines the need to take sex differences into account in Alzheimer’s research and treatment, the researchers say, because the disease can progress differently in men and women and therefore may require a tailored approach, said Dr. Gan.

By identifying the role of immune pathways such as cGAS-STING in the progression of Alzheimer’s disease, especially in individuals with high-risk genetic variants, the researchers hope to open the door to new strategies for treatment – ​​and possibly prevention.