The world's population is aging, and dementia and Alzheimer's are becoming more common. Alzheimer's also tends to impact more women than men. Scientists have now identified a genetic variant that can raise the risk of developing Alzheimers in carriers. They used a mouse model to show that these variants lead to a deleterious inflammatory reaction in the immune cells of the brain, known as microglia. But this inflammatory response happened much more in female mice compared to males. The findings have been reported in Neuron.
For decades, scientists have relied on mouse models to learn more about human health and disease. But in many cases, researchers used male mice to avoid the complicating factors that are presented by hormonal cycles. But this study has highlighted the importance of considering sex differences when performing research studies in general, and in Alzheimer's disease (AD) studies in particular.
Previous work has revealed that a genetic variant known as APOE4 can raise the risk of Alzheimer's in carriers, and particularly in those who carry two copies of that variant instead of others, such as APOE3. The APOE4 variant also raises women's Alzheimer's risk more than men.
In this work, the researchers assessed APOE4 in the context of another Alzheimer's-linked genetic variant found in a gene called TREM2.
"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," noted senior study author Dr. Li Gan, director of the Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell Medicine, among other appointments. "Our goal was to combine these risk factors to highlight what pathways are altered when the risk of disease is strongest."
Dr. Gan is featured in the video below.
The research team engineered mouse models that carried human versions of the TREM2 variant, called R47H, along with APOE4. The TREM2 R47H variant is thought to raise Alzheimer's risk by as much as 4.5 times. The mice also carried a genetic mutation that causes tau protein to accumulate. These protein clumps are often seen as people experience cognitive decline during aging. In this mouse model, the clumps appeared around ten months of age, which corresponds to human middle age.
The investigators determined that in female mice that carried the TREM2 R47H variant and APOE4, there was significant damage in a part of the brain that is involved in learning and memory. This damage was not seen in male mice. The tau clumps were also more severe compared to mice that did not carry genetic mutations other than the one that causes the clumps to appear.
Additional work showed that this brain damage was caused by immune cells in the brain known as microglia. Usually microglia are protective, but they stopped functioning normally and were no longer able to divide; they entered a state called senescence. They stopped performing their typical functions, and began to release inflammatory signals related to a biochemical pathway called cGAS-STING.
The genetic factors combined to significantly activate the cGAS-STING pathway. But when the pathway was suppressed, the researchers were able to reduce the harm and aging in the mouse brains.
Now that scientists have implicated this pathway in Alzheimer's, it may eventually improve Alzheimer's treatments for patients.
Sources: Weill Cornell Medical College, Neuron