Study Uncovers Sex-Specific Alzheimer’s Risk Linked to Genetic Variants

New research from Weill Cornell Medicine has uncovered how two genetic variants, known to increase the risk of Alzheimer’s disease (AD), work together to trigger a harmful inflammatory response in the brain—particularly in females. The study, published in Neuron, highlights the importance of understanding sex differences in Alzheimer’s research and may lead to more precise and effective treatments for the disease.

The study explained that Alzheimer’s disease affects millions of people worldwide, and women are disproportionately impacted, developing the disease at nearly twice the rate of men. Scientists have long been searching for the biological reasons behind this increased vulnerability in females. The Weill Cornell team, led by Li Gan, PhD, has now identified key cellular activities that go awry when two high-risk genetic variants, APOE4 and a variant of TREM2, are present together in females. These variants, both linked to increased Alzheimer’s risk, appear to provoke a damaging inflammatory response in the brain’s immune cells.

“Although these are two of the strongest risk factors for AD, little is known about how they enhance disease risk and they have not been often studied together,” said Dr. Gan, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine. “Our goal was to combine these risk factors to highlight what pathways are altered when the risk of disease is strongest.”

Dr. Gan and her team, including lead author Gillian Carling, PhD, conducted their research using a preclinical mouse model carrying human versions of APOE4 and TREM2 R47H, a rare genetic variant that raises the risk of AD by two to 4.5 times. The mice also carried a mutation that leads to the development of tau protein clumps, a hallmark of Alzheimer’s disease closely associated with cognitive decline. The researchers examined the brains of these mice at nine to 10 months of age, equivalent to middle age in humans, to assess how these genetic variants impacted brain health.

The study revealed that female mice, but not male mice, carrying both the APOE4 and TREM2 R47H variants exhibited significant damage to the brain region responsible for memory and thinking. This damage included more severe clumping of tau proteins compared to mice without these genetic risk factors.

The researchers attributed this brain damage to malfunctioning immune cells in the brain, known as microglia. Microglia usually act as protectors, cleaning up damaged cells and protein clumps, but in this case, they became “senescent,” or aged, losing their ability to function properly. Rather than helping to clear the brain of harmful proteins, these aged microglia lingered and released inflammatory chemicals through a pathway called cGAS-STING. Notably, this damaging immune response was significantly more pronounced in the female mice, aligning with prior research that shows APOE4 presents a stronger risk for women than men.

“Our research showed that when the two Alzheimer’s risk factors are combined in females with tau aggregates, the cGAS-STING pathway becomes highly activated,” said Dr. Carling. Importantly, the team found that suppressing this harmful pathway reduced inflammation and rescued the aging phenotype in microglia, suggesting a potential therapeutic target for future treatments.

According to the researchers, the study reinforces the need to consider sex differences in Alzheimer’s research and treatment strategies as the disease may progress differently in men and women. They explained that the identification of the cGAS-STING pathway’s role in the progression of Alzheimer’s, particularly in individuals with high-risk genetic variants, offers new hope for developing strategies aimed at treatment and potentially prevention.