Tau Blood Biomarkers May Signal Faster Cognitive Decline in Women

Women are twice as likely to develop Alzheimer’s than men, but scientists don’t know why. 

The knowledge gap is driven by the historical exclusion of women from research studies. Prior to a 1993 law requiring the inclusion of women in federally funded research, scientists didn’t have any data on how sex influences disease biology let alone drug responses. 

Even today, many studies of Alzheimer’s biomarkers and treatments fail to account for sex differences. Clinical trials for Leqembi and Kisunla did not conduct a sex-stratified analysis, leaving some scientists questioning whether the drugs work equally well in women. 

In recent years, researchers have discovered that with age, healthy women form tau tangles — a hallmark of Alzheimer’s that puts them at risk of cognitive decline sooner — faster than men. With pTau-217 blood tests now used to aid Alzheimer’s diagnoses, including one that’s FDA-cleared, would it also show these sex differences? 

A recent study published in JAMA Neurology builds on the evidence, finding that elevated levels of the blood biomarker pTau-217 signal more tau tangles and faster cognitive decline in women’s brains.

“Amyloid sets the stage for all these downstream tau processes to occur,” the study’s author Gillian Coughlan, PhD, an instructor in neurology at Massachusetts General Hospital, told Being Patient. “Women seem to have this stronger response to the amyloid where we’re seeing more tau accumulation.” 

Sex determines the speed of tau tangles

Coughlan’s team analyzed imaging and biomarker data pooled from over 1,200 cognitively healthy adults in their 70s from five different study cohorts — four following healthy older adults and one Alzheimer’s prevention trial. 

In the first part of their analysis, Coughlan and her team wanted to see whether sex influenced the blood biomarker pTau-217, which provides a measure of beta-amyloid plaques and tau in the brain. 

Coughlan and her team focused on people with high levels of beta-amyloid plaques in the brain, who are most at risk of developing Alzheimer’s-related cognitive decline. Combining all the data together, there was no difference in pTau-217 levels between men and women. But looking at each individual cohort, in three of them, women had higher levels of pTau-217 in their blood. 

Women also had more tau tangles in the brain at similar pTau-217 levels. Over three-and-a-half years, women accumulated tau faster, as measured by tau PET scans, than men — although which regions developed tangles faster differed across the study cohorts. 

Tau tangles start accumulating within a region of the brain called the medial temporal lobe. From there it spreads to other regions of the brain, called the neocortex, important for higher-level processing of information. The spreading process “seems to have happened faster in women relative to men,” said Coughlan.

In two of the three cohorts that tracked cognitive health, higher levels of pTau-217 also led to faster cognitive decline in women.  

Differences in age, geographic location, education and genetic risk factors among the study cohorts may account for some of the differences between the different study cohorts the researchers looked at.

The study isn’t able to explain why these sex differences occur. Coughlan said that early or premature menopause, starting hormonal therapy late, and factors related to women carrying two copies of the X chromosome might all contribute to the increase in risk. 

What does it mean?

Coughlan’s research suggests that the same levels of pTau-217 might mean more risk for women, since they tend to have more tangles. Sarah Banks, a clinical neuropsychologist and associate professor at UC San Diego, who wasn’t involved in the research, wrote to AlzForum that the study “highlights the need to pay close attention to sex when analyzing biomarker data in Alzheimer’s research.” 

Since there aren’t any proven treatments that prevent cognitive decline in people at risk of Alzheimer’s, neurologists currently recommend against testing people who are cognitively healthy. 

Still, the study provides more information about the potential trajectory of the disease. “If women are starting the disease process earlier, and it’s a more aggressive disease process overall, then clinicians need to be aware,” said Coughlan.