Sex-Based Genetic Risk and Immune Response Differences in Alzheimer Disease: Li Gan, PhD

WATCH TIME: 4 minutes

"Female microglia carrying these 2 risk genes become aged faster, exhibiting senescence phenotypes, which is different from male immune cells with the same genetic risk."

Alzheimer disease (AD) impacts millions of patients globally, with women disproportionately affected as prior research has shown that nearly twice as many women develop the disease compared with men. In a new preclinical study, findings revealed that female mice with both APOEe4 and TREM2 R47H exhibited significant damage to the brain region. Published in Neuron, these results highlight the importance of considering sex differences in AD research which could lead to more precise and effective treatments.^1,2

The study, conducted by senior author Li Gan, PhD, and colleagues, established mouse models for AD carrying human versions of APOEe4 and TREM2 R47H, 2 genetic variants that both confer high risk of AD. Authors noted that the mice also carried a mutation that led to the development of clumps of tau protein, abundant in AD brains and closely associated with cognitive decline in patients. Thus, investigators assessed the mice at 9-10 months of age, which was noted as roughly equivalent to middle age in humans, to explore how the genetic variants impacted brain health.

Gan, the director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine recently sat down with NeurologyLive^® in an interview to further discuss how APOEe4 and TREM2 mutations affected immune responses, observed in male and female mouse models, differently in AD. Gan, who also serves as a professor or neuroscience at Weill Cornell Medicine, talked about the limitations of using mouse models to study AD, and how human-derived models can enhance research accuracy. In addition, she spoke about why sex stratification may be important when conducting AD clinical trials and assessing biomarker changes.

REFERENCES
1. Carling GK, Fan L, Foxe NR, et al. Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model. Neuron. Published online September 24, 2024. doi:10.1016/j.neuron.2024.09.006
2. Alzheimer’s Genetic Risk Factors Spark Inflammation in Females. News Release. Weill Cornell Medicine. Published September 20, 2024. Accessed October 10, 2024. https://news.weill.cornell.edu/news/2024/09/alzheimer%E2%80%99s-genetic-risk-factors-spark-inflammation-in-females