Weill Cornell Medicine investigators have found that two genetic variants that confer high risk of Alzheimer's disease (AD) together trigger a harmful inflammatory response in the brain's immune cells, particularly in females, in a preclinical model. The findings, published Sept. 30 in Neuron, emphasize the importance of considering sex differences in Alzheimer's research - a step that could ultimately lead to more precise and effective treatments.
AD affects millions of people worldwide, with women disproportionately impacted - nearly twice as many females develop the disease compared with males. To advance therapeutic approaches, investigators 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 compared with men.
The current study zeroed in on cellular activities that go awry when APOE4 and a variant of the TREM2 gene, which also raises AD risk, are present together in females. Because the proteins encoded by these genes have a variety of functions in cells, it has been unclear how the particular variants contribute to a vulnerability to the disease. 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.
Our goal was to combine these risk factors to highlight what pathways are altered when the risk of disease is strongest." Dr. Li Gan, senior author director.
