Researchers at Weill Cornell Medical Center report that genes linked to a higher risk of Alzheimer’s disease appear to interfere with cognitive function more often in women, a difference that may be driven by how immune cells in the brain respond. The study, which appears in the journal Neuron, adds a new layer to the growing evidence that sex and genetics interact in brain aging.
Alzheimer’s disease affects millions worldwide and places a disproportionate burden on women, who are affected at roughly twice the rate of men. To understand why the gender gap exists, scientists examined genetic contributors to disease onset and progression, focusing on how specific gene variants shape brain health and resilience over time.
In a controlled study, researchers used rats engineered to carry human versions of the APOE4 gene and the TREM2 R47H variant. These rare genetic changes markedly raise the risk of developing Alzheimer’s disease. The findings showed that female rats with these mutations sustained more severe damage in a brain region central to thought and memory, with noticeably larger accumulations of toxic tau proteins. The pattern did not appear in male rats, underscoring a sex-specific effect tied to genetic risk.
The observed pattern points to microglia, the brain’s resident immune cells, as a key driver of the sex difference. When APOE4 and TREM2 carry the R47H mutation, microglia lose efficiency in clearing damaged cells and protein debris. Instead, they shift toward a state that promotes inflammation rather than repair.
Microglial impairment shifts the brain’s balance toward damage. With impaired cleanup and a surge of inflammatory signals, neural circuits that support memory and executive function can deteriorate more rapidly in women carrying these variants. The result is a greater vulnerability to tau pathology, a hallmark of Alzheimer’s, in the regions that govern learning and memory.
Tau proteins normally stabilize microtubules in neurons, but in Alzheimer’s they become toxic when they accumulate as tangles. The study found larger tau accumulations in affected female brains, correlating with worse cognitive outcomes in the animal models. These tauopathies are a key target for treatments in development, making the study’s sex-specific angle particularly relevant.
Beyond tau, APOE4 is known to disrupt lipid transport and immune signaling in the brain. TREM2 plays a role in sensing cellular debris and coordinating microglial responses. The R47H variant alters these functions, creating a scenario where microglia either fail to clear waste or actively contribute inflammatory damage.
The research suggests that the intersection of these two gene variants with female biology heightens the risk landscape for Alzheimer’s. This insight supports a personalized approach to prevention and therapy, where sex-specific biology and genetic risk are considered when evaluating treatment options.
While the results illuminate a possible mechanism, they come from animal models. Translation to humans requires replication in diverse populations and careful study of how these pathways operate in people over time. The findings do not imply an immediate cure but point to new directions for drugs aimed at modulating microglial function and tau spread.
Researchers emphasize that the work underscores the need for inclusive studies that examine sex differences in genetic risk for neurodegenerative diseases. Better understanding of microglial behavior and its impact on women could guide the development of therapies that protect memory and cognitive health across populations.
Overall, the work contributes to a broader picture of how genes and brain immunity shape Alzheimer’s risk. It adds urgency to pursuing therapies that can recalibrate immune cells in the brain and curb tau pathology, with careful attention to how these mechanisms may differ for men and women.