United States: An international team of Weill Cornell Medicine investigators has discovered that two genetic variants that define the high risk of Alzheimer’s disease or AD in combination lead to blood-brain barrier disruption and a toxic inflammatory response in glioblastoma cells, especially in females, in a preclinical model.
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The results, reported September 30 in the journal Neuron, suggest that future Alzheimer’s research should take sex more seriously – a move that could one day translate into better treatments., particularly in females, in a preclinical model.
It is estimated that AD is present in more than 50 million people globally, and while men make up more than 40 percent of those affected, women are most frequently diagnosed – the risk of the disease being two times higher for them than for men, neurosciencenews.com reported.
Thus, to enhance therapeutic options, the investigators are interested in identifying the origins of these differences in susceptibility.
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According to the researchers, “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.”
As senior author Dr. Li Gan, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine stated, “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,” neurosciencenews.com reported.
“Our goal was to combine these risk factors to highlight what pathways are altered when the risk of disease is strongest,” she added.
The research team, which also included the lead author Dr. Gillian Carling, a graduate student in the Weill Cornell Medicine Graduate School of Medical Sciences at the time of the study, suggested that mouse models for AD which were carrying human versions of APOE4 and TREM2 R47H, a rare variant that increases AD risk 2-4.5-fold.
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The researchers sourced the break in these female brains to the brain’s tiny immune cells known as microglia.
Under normal circumstances, microglia are known to focus on preserving the entirety of the brain, but they are ‘senescent’, which is a term used to describe cells that stop functioning optimally because of age.
Rather than clearing up dead cells and clumped proteins, these aged microglia stick around and emit inflammatory substances through cGAS, an STING pathway.
Notably, the study observed that these negative impacts were worse in female mice, reflecting the position that APOE4 is more dangerous to females than males.
The study stresses for future research and treatment of Alzheimer’s; with the help of sex differences, the authors of the study noted that Alzheimer’s might have different ways of progression in men and women and thus may need different strategies, explained Dr. Gan.