Polycystic ovary syndrome (PCOS), recently renamed polyendocrine metabolic ovarian syndrome (PMOS), is best known for its effects on reproductive health. But the condition extends beyond the ovaries, with metabolic abnormalities such as insulin resistance affecting many people with the syndrome. Now, researchers are investigating whether these abnormalities could also have implications for the brain.
A recent study published in the Journal of the Endocrine Society investigated the evidence linking PMOS with cognitive changes and dementia. DDN spoke with Ricardo Azziz, a professor of reproductive endocrinology and gynecology at the University of Alabama at Birmingham and senior author of the study, to understand what the research reveals about the potential relationship between PMOS and brain health, the role insulin resistance might play, and what evidence is needed to determine whether the syndrome affects long-term cognitive function.
Looking for signs in the brain
Researchers have begun investigating whether the metabolic and hormonal changes associated with PMOS could also affect the brain. One area of interest is brain glucose metabolism, which provides energy for neuronal activity and has been linked to insulin resistance in other populations.
In a 2015 study published in PLOS ONE, researchers investigated this possibility by using positron emission tomography (PET) to measure brain glucose uptake in seven women with PMOS and 11 women without the condition. They found reduced glucose uptake in several brain regions among the women with PMOS, with some of these reductions associated with greater insulin resistance.
The study offered an early indication that the metabolic abnormalities associated with PMOS might extend to the brain. However, it did not establish whether the differences affected cognitive function or had implications for long-term brain health.
A 2024 study published in Neurology took this investigation further by examining cognitive performance and brain structure in middle-aged women with PMOS. Researchers analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, finding that women with PMOS generally performed more poorly on tests of verbal memory, executive function, and category fluency than women without the condition.
In a smaller subgroup who underwent brain imaging, women with PMOS also had lower white matter integrity, a measure of the organization of nerve fibers that connect different brain regions.
These findings suggest that the metabolic and hormonal features of PMOS might influence brain health over time. However, neither study established whether the syndrome causes these changes or explained the mechanisms involved.
Could insulin resistance connect the two?
One possible explanation for these findings is insulin resistance, a defining metabolic feature of PMOS that affects 75 to 95 percent of patients. When cells respond less effectively to insulin, the body often compensates by producing more of the hormone. This excess insulin, known as hyperinsulinemia, contributes to several of the syndrome's reproductive and metabolic features, including increased androgen production by the ovaries.
Insulin also has important functions in the brain, where it participates in signaling pathways involved in neuronal function, synaptic plasticity, and memory. Insulin resistance, in the context of diabetes, has been linked to impaired neuronal metabolism and synaptic function, potentially leading to cognitive decline. Researchers have therefore questioned whether altered insulin signaling could help explain some of the cognitive and metabolic differences observed in people with PMOS.
However, there are important differences between insulin resistance in PMOS and in other metabolic conditions. While type 2 diabetes can eventually involve declining insulin production as pancreatic beta cells lose function, insulin resistance in PMOS typically occurs alongside hyperinsulinemia. “We can't equate just standard insulin resistance with failing beta cell function,” said Azziz.
Whether insulin resistance in PMOS has the same effects on brain metabolism and cognitive function as insulin resistance in other conditions remains unclear. Obesity, type 2 diabetes, vascular health, and other factors could also contribute to the cognitive differences observed in some studies. Larger, long-term studies are needed to determine whether PMOS itself is associated with changes in brain health, or whether these associations reflect shared metabolic risk factors.
What about Alzheimer's disease?
Several features of PMOS, including insulin resistance, chronic inflammation, hormonal disturbances, and an increased risk of cardiovascular disease, are also associated with Alzheimer's disease. People with PMOS may therefore experience some of the metabolic and hormonal changes implicated in cognitive decline earlier in life. Researchers have consequently begun investigating whether the syndrome could increase vulnerability to Alzheimer's disease and related dementias.
In their review, Azziz and his colleagues examined evidence spanning cognitive testing, brain imaging, and biomarkers associated with neurodegeneration. Some studies suggest that people with PMOS experience differences in memory, attention, and executive function, while others have identified changes in proteins associated with Alzheimer's disease. However, they found that evidence directly linking PMOS to a higher risk of developing dementia is still limited and inconsistent.
“We should not jump to conclusions to say that PMOS patients have a higher risk of Alzheimer's disease. But what we can say is that both seem to be linked to metabolic dysfunction,” Azziz said.
A key problem is that much of the available evidence comes from small studies, many of which lack appropriate control groups. This research gap partly reflects the chronic underfunding of PMOS research, despite the syndrome’s prevalence and associated health burden.
Azziz and his colleagues are now beginning to design prospective and retrospective studies to investigate whether the association between PMOS and cognitive decline holds in larger groups. They are exploring existing datasets, including the UK Biobank and the Nurses' Health Study, with the aim of examining a broader range of long-term outcomes, including diabetes, heart disease, stroke, dementia, and mental health conditions.
These studies will be essential for helping researchers understand how PMOS affects women beyond their reproductive years, including whether the metabolic changes associated with the syndrome have consequences for brain health and other aspects of aging.
