Investigators have discovered that two genetic variants linked to a high risk of Alzheimer’s disease (AD) trigger a damaging inflammatory reaction in the brain’s immune cells, especially in females, when studied in a preclinical model.
Researchers from Weill Cornell Medicine have found that certain genetic factors that heighten the risk of Alzheimer’s disease (AD) combine to provoke a detrimental inflammatory response within the immune cells of the brain, predominantly affecting females, in a preclinical setting.
The research, released on September 30 in Neuron, highlights the necessity of considering gender differences in Alzheimer’s studies—an approach that may ultimately lead to more targeted and effective treatments.
AD impacts millions globally, with a significant disproportion noted in women—nearly double the number of females are diagnosed compared to males. To enhance treatment methods, researchers are investigating the underlying reasons for these differences in susceptibility. Prior research has indicated that the APOE4 gene variant amplifies AD risk more significantly in women than in men. The current study focused on how cellular processes are disrupted when both APOE4 and a variant of the TREM2 gene are present in females, both of which are known to increase AD risk. As these genes play multiple roles in cellular function, understanding how these specific variants contribute to disease vulnerability has been challenging.
“Even though these are two of the most significant AD risk factors, there is limited understanding of how they increase the likelihood of developing the disease, and they haven’t been frequently studied together,” explained senior author Dr. Li Gan, who leads the Helen and Robert Appel Alzheimer’s Disease Research Institute and holds the Burton P. and Judith B. Resnick Distinguished Professorship in Neurodegenerative Diseases at Weill Cornell Medicine. “We aimed to combine these risk factors to identify the pathways that are altered when the risk of developing the disease is heightened.”
Dr. Gan and her team, which included lead author Dr. Gillian Carling, who was a graduate student at Weill Cornell Medicine at that time, created mouse models for AD that incorporated human versions of the APOE4 and TREM2 R47H variants, the latter being a rare variant that increases AD risk by 2-4.5 times. The mice were also genetically modified to develop tau protein clumps, which are prevalent in AD and strongly linked to memory loss in patients. To determine how these genetic factors affected brain health, they examined the mice at 9-10 months of age, approximately equivalent to middle age for humans.
The study revealed that female mice carrying both APOE4 and TREM2 R47H exhibited notable damage in the brain region critical for thinking and memory, unlike their male counterparts. This damage was characterized by more extensive tau protein aggregation compared to mice lacking these genetic combinations.
The research team attributed the damage observed in female brains to immune cells known as microglia. Under normal circumstances, microglia protect the brain, but in this instance, they became “senescent,” meaning they aged and lost their functionality. Instead of eliminating damaged cells and protein aggregates, these dysfunctional microglia remained in place and released inflammatory substances via a pathway known as cGAS-STING. Significantly, the study noted that these harmful outcomes were more pronounced in female mice, supporting existing evidence that APOE4 presents a stronger risk for women than men.
“Our study indicated that when both Alzheimer’s risk factors are present in females with tau aggregates, the cGAS-STING pathway is significantly activated,” Dr. Carling highlighted. By inhibiting this harmful pathway, the researchers were able to reduce detrimental inflammatory factors and reverse aging-related changes in microglia.
The findings of this study emphasize the necessity of accounting for sex differences in Alzheimer’s research and treatment, according to the researchers, as the disease may evolve differently in men and women, potentially requiring customized treatment strategies, as noted by Dr. Gan.
By examining the immune pathways like cGAS-STING in the advancement of Alzheimer’s—especially in those with high-risk genetic variants—the researchers aspire to pave the way for new treatment and preventive strategies.
