A new study led by researchers at UC San Diego shows a certain protein detected in the blood can provide decades of early warning that a person is at an increased risk of developing dementia later in life.

The finding has the potential to provide a longer runway to make the lifestyle changes that can help reduce risk, and could be used to better identify subjects who could benefit from participating in clinical trials seeking to prevent or treat neurodegenerative disease.

Published Tuesday in the medical journal JAMA Network Open, the study pulls off a bit of time travel by analyzing frozen blood samples collected in the 1990s by participants in the Women’s Health Initiative Memory Study, a research effort that examined the effects of hormone replacement therapy on dementia in post-menopausal women.

Though the initial hypothesis was that women age 65 and older taking estrogen or estrogen and progestin would gain protection against chronic disease, the opposite proved true, with results published in 2003 concluding that “estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women age 65 or older.”

Subsequent research clarified that earlier hormone treatment, before age 60, does not carry the same risks and can be useful for the treatment of menopause symptoms.

More recently, researchers have zeroed in on better signals of dementia with a protein called plasma phosphorylated tau 217 — p-tau217— a substance that supports the stability of structures in the brain, but that can become tangled when overactivated by phosphates.

Since roughly 2020, p-tau217 has been seen as an accurate biomarker of developing dementia, including Alzheimer’s disease. But this observation had not yet been made when the memory study began enrolling participants at 39 sites across the nation in 1996.

Only recently, notes Aladdin Shadyab, the study’s first author and an associate professor specializing in women’s health and aging at UC San Diego, did the U.S. Food and Drug Administration approve a scientific testing tool called an assay for tau 217.

“The field has moved so rapidly that by the time we had the blood samples in the lab, a p-tau217 assay was available,” Shadyab said. “We were very fortunate that we got to have it measured.”

It is not just that labs can now test large numbers of blood samples for this particular protein, but also that those who collected samples and performed follow-up from the 1990s through 2021, faithfully recorded the results of cognitive assessments.

This recordkeeping and the long-term investment in preserving original “baseline” blood samples allowed Shadyab and a wide-ranging group of colleagues to retroactively look for a correlation between the presence of p-tau217 and dementia diagnosis.

They selected 2,766 records from the memory study’s 7,479 participants, choosing 1,311 diagnosed with dementia or mild cognitive impairment to compare with 1,455 participants who were not diagnosed.

The results showed that women eventually diagnosed with either of these two conditions — 849 with mild cognitive impairment and 752 with dementia — had larger amounts of p-tau217 in their initial blood sample way back in the mid-to-late 1990s.

Overall, Shadyab said, understanding that this biomarker can be observed many years before dementia or mild cognitive impairment symptoms appear offers a chance for intervention.

“What we’re showing is that with a simple blood test we can detect who is at risk of future dementia decades in advance,” Shadyab said. “Women who had elevated levels of this biomarker when they were cognitively healthy were at a threefold higher risk of future dementia up to 25 years later.”

Margaret Gatz, a professor of psychology at the University of Southern California, whose work focuses on the risk and protective factors of Alzheimer’s disease and associated types of dementia, said that the paper’s results “give important support” to the use of biomarkers to identify dementia risk early.

“Further research about the relationship of plasma p-tau217 to potentially modifiable risk factors for dementia could be enormously helpful in pointing to health and lifestyle choices that people can make years before the typical onset of dementia that could reduce their personal risk,” Gatz said in an email.

High blood pressure, obesity, physical inactivity and smoking have long been lifestyle factors associated with higher dementia risk.

More work is underway to determine what triggers p-tau217 to appear.

“We are actually working on papers right now, looking at what the modifiable behaviors are that relate to changes in these blood-based biomarkers over time,” Shadyab said.

While the subjects in this study were all women, the researcher, who holds a doctorate in epidemiology and works in UCSD’s Herbert Wertheim School of Public Health and Longevity Science, said there is no reason to think that it is not valid for men.

“There have been other studies that have shown associations of p-tau217 with dementia in men, so these findings add to the converging evidence supporting the utility of this biomarker in both men and women,” Shadyab said.

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