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A study published in JAMA Network Open looks at plasma p-Tau217 levels in blood and dementia risk.
Prof Eef Hogervorst, Professor of Biological Psychology, and Director of Dementia Research, National Centre for Sports and Exercise Medicine, Loughborough University, said:
“This study had taken bloods from 2766 women who had been recruited in a clinical trial in 1996/1999 and who were then followed up until 2021 to establish whether plasma p-tau217 (a biomarker for Alzheimer’s disease or AD) was associated with taking hormone treatment (HT). This HT could be combination treatment (consisting of estrogen and progesterone for women with an intact womb); or estrogen alone (for women who had undergone hysterectomy).
“The authors found that increased levels of the biomarker gave a higher risk for dementia, and this was significantly higher in women who had been prescribed combination HT. This was not the case in women who had been given estrogen alone. This association was stronger for women over 70, in white women and those carrying the APOE e4 genotype, a genetic risk factor for dementia. There was also an increased risk for prodromal dementia, called mild cognitive impairment, but this was not found in black women. This may be associated with smaller numbers having been included in the study.
“It is not the first time that the Women’s Health Initiative Memory Study (WHIMS) reported such effects. In fact, their 2002/2003 papers suggested a doubled risk of dementia with combination HT, already early in the clinical trial which was stopped early, because of these and other increased risks (eg breast cancer). Importantly this effect was only seen in older women, over age 65, to whom normally HT would not be prescribed. However, these papers resulted in many women stopping HT, also those who were close to the average age at menopause, around 51 years of age.
“In 2017, Espeland reported a follow-up analyses of this cohort showing that women who had been prescribed HT at an earlier age (between 50-54 years of age, so at the time when most women would take HT for menopausal complaints, the so called WHIMSY sub-study) showed no effect of taking HT on cognitive function or decline. This was measured 6-7 years after the 5 -7 year HT trial had stopped. At this point, those women were on average 67 years of age. Similar results were found in other clinical trials like KEEPS and ELITE, showing good safety -but no cognitive benefits- up to 10 years of combination HT in relatively healthy women who had been given HT close to the average age at natural menopause.
“However, global cognition (which is used to detect dementia) had declined in the older women of the WHIMS study, who were then around 70 years of age and had started treatment after age 65. This was worse in women who already had lower baseline cognition. Another analyses of this cohort by Coker et al in 2010 had reported that in the older women, 8 years after the initial inclusion in the WHIMS study, MRI brain scans showed trends for reduced hippocampal and frontal volume in combination HT users. This may suggest that combination HT worsens the effects on existing pathology and low cognitive reserve related to later life dementia risk.
“The current WHIMS study adds to that data. It confirms our meta-analyses of National Registry data showing increased AD risk in older women (after age 60) using combination HT (Kuck et al., 2024). We also found slight increased AD risk in women closer to the age of menopause when this had been prescribed for more than 10 years. More studies need to be done to investigate who is at risk of cognitive decline and dementia taking combination HT for longer period of time. Vasomotor flushes severity has been associated with dementia in later life. However, taking HT for 5 years or less, when close to the age at menopause in midlife, was not seen to increase cognitive decline or AD risk in clinical trials or most National Registry data.
Prof Tara Spires-Jones, Professor of Neurodegeneration at the University of Edinburgh, Division Lead in the UK Dementia Research Institute, and Past President of the British Neuroscience Association said:
“This is a well-conducted observational study by Dr Shadyab and colleagues at the University of California San Diego showing that race, older age, and use of hormone replacement therapy (HRT) can all affect how effective a blood test is at predicting cognitive decline and dementia in women. The blood test detects a form of the tau protein (p-tau217) that accumulates in the brain during Alzheimer’s disease. In this study, authors looked at data from 2766 women who participated in a randomized trial of oestrogen only HRT, oestrogen plus progestin HRT, or placebo and calculated how well p-tau217 in a blood sample at the beginning of the study predicted the risk of developing cognitive impairment or dementia over the following 25 years. In agreement with many other studies, participants with higher levels of p-tau217 in their blood were more likely to develop cognitive impairment or dementia. This study had several strengths and advantages over previous data including the long follow-up time showing that this test indicates up to 25 years in advance that someone might develop dementia. Another strength was looking at HRT use, with authors finding a stronger association of the p-tau217 blood test with dementia in people who took oestrogen plus progestin but not oestrogen alone. Further, authors looked at the effects of race and age showing that p-tau217 in blood was more strongly associated with risk of dementia in white women compared to black women and in women older than 70 compared to those younger. Understanding how age, race and HRT might influence the interpretation of this type of blood test is important for future clinical trials. However, there are important limitations to consider. This type of data cannot explain why HRT and race influence the effectiveness of this test, which are important questions for future work. While p-tau217 in blood is now well established to be a good marker of brain changes that occur early in Alzheimer’s disease, not everyone with these brain changes will go on to develop dementia, so a positive test is not a guarantee of developing disease.”
Prof Masud Husain, Professor of Neurology, University of Oxford, said:
“This is an impressive study that uniquely has been able to analyze blood samples from women followed up for upto 25 years. The findings show that the level of p-tau 217 in the blood provides an index of the risk of developing dementia in the future. These results add further support for growing evidence that testing p-tau 217 in blood might be an important way to screen for people who are most at risk of dementia, years before a diagnosis is made.”
Dr Sheona Scales, Director of Research at Alzheimer’s Research UK, said,
“Women are twice as likely to be affected by dementia, but we do not understand why there is this difference.
“In this well conducted large study involving nearly 3000 women who had no issues with memory and thinking, researchers showed that high levels of a protein in the blood, called ptau-217, could predict dementia or MCI up to 25 years before symptoms begin to show. This study adds to growing research exploring whether blood‑based biomarkers could identify who may be at higher risk of dementia decades before symptoms develop.
“The researchers also found that blood levels of p-tau217 could be affected by many different factors, such as hormone replacement therapy, ethnicity, APOE 4 status and age. This highlights the need for more research to understand how these interact over a woman’s lifetime and in more diverse groups of people.
“As it stands today, these blood tests are fast becoming a powerful tool as part of a standard dementia diagnosis assessment. But we are still learning about how these tests work, especially in people who don’t have the signs and symptoms of MCI or dementia, so they are not currently a standalone test.
“While the findings are promising, more research is needed before these tests could be used to reliably predict dementia in routine healthcare.
“If you are concerned about your memory, you should speak to your GP.”
Prof Richard Unwin, Professor of Disease Proteomics, University of Manchester, said:
“The headline of this press release is misleading, in my view.
“The blood test does not ‘predict’ dementia early as one would commonly understand it; if you get a result above a certain level, it does not tell you if you are, or not, going to develop dementia with any degree of accuracy.
“We know that there are changes in the brain for decades prior to the appearance of visible dementia symptoms, and one of those changes is the build-up of the molecule pTau217. The researchers in this study have measured the levels of pTau217 in the blood of a large number of women and then tracked them for an average of 15 years (longest 25 years) to see who developed either dementia or a condition called mild cognitive impairment.
“They show that if you have substantially above-average levels of pTau217 then you are more likely to develop dementia than someone with lower levels. It does not predict that you will get dementia. This increase in risk is probably slightly higher than the dementia risk associated with smoking or heavy alcohol consumption and this probably reflects these early pre-symptomatic changes in the brain.
“This is useful information – although it is not a prediction of a future dementia diagnosis, it would give an individual the opportunity to manage risk factors under their control, for example give up smoking and drinking alcohol, exercise, and maintain a healthy weight.”
Dr Ivan Koychev, Clinical Associate Professor in Neuropsychiatry, Imperial College London, said:
“This is a well conducted study that adds to growing evidence that the blood biomarker p-tau217 is linked to future Alzheimer’s disease–related changes in the brain. However, the claim that a blood test could predict dementia 25 years before symptoms should be treated cautiously. The study shows that higher p-tau217 levels in older women were associated with a higher risk of developing mild cognitive impairment or dementia during up to 25 years of follow up, but this reflects the length of observation in the cohort rather than a test that can reliably predict the disorder decades in advance for an individual. It is also important to note that mild cognitive impairment is not dementia, and many people with MCI do not go on to develop dementia. In studies like this, combining MCI and dementia as a single outcome can make the association appear stronger, but these are clinically distinct stages with different implications for patients and healthcare systems. MCI represents a risk state rather than established disease, so interpreting results as prediction of dementia needs caution, particularly when considering how such biomarkers might be used in real world clinical decision making. The bigger question now is how these biomarkers translate into real world clinical practice. Dementia in older adults is often caused by several overlapping brain diseases, and research cohorts are not always representative of routine healthcare populations; p-tau217 also only tells you about Alzheimer’s disease specifically. Understanding how tests like p-tau217 perform in everyday clinical settings, and whether they meaningfully improve diagnosis and care in a cost effective way, will be critical before they can be widely used.”
‘Plasma Phosphorylated Tau 217 and Incident Mild Cognitive Impairment and Dementia in Older Women’ by Aladdin H. Shadyab et al. was published in JAMA Network Open at 15:00 UK time on Tuesday 10th March.
DOI: 10.1001/jamanetworkopen.2026.1295
Declared interests
Prof Eef Hogervorst: I was advisor for NICE on HRT and dementia for the 2024 updated UK Guidelines and for ESHRE (early menopause) for the 2016 European Guidelines.
Prof Tara Spires-Jones: I have no conflicts with this study but have received payments for consulting, grant reviews, scientific talks, or collaborative research over the past 10 years from AbbVie, Sanofi, Merck, Scottish Brain Sciences, Jay Therapeutics, Cognition Therapeutics, Ono, Novo Nordisk, Eisai, and Boehringer Ingelheim, and direct a company Spires-Jones Neuroscience, Ltd to act as a consultant. I am also Charity trustee for the British Neuroscience Association and the Guarantors of Brain and serve as scientific advisor to several charities and non-profit institutions.
Prof Masud Husain: “I don’t have any conflict of interest.”
Dr Sheona Scales: “No conflicts of interest”
Prof Richard Unwin: I’m a Co-founder and shareholder of Complement Therapeutics, although they do not do any work in the Alzheimer’s/neurodegeneration space.
Dr Ivan Koychev: Ivan Koychev is the co-lead on the NIHR, Alzheimer’s Research UK, Alzheimer’s Society and People’s Lottery Blood Biomarker Challenge grant which evaluates the utility and health economics of blood biomarkers in real-world NHS dementia care settings. He has received grant funding for an investigator-initiated study from Novo Nordisk. He has received consultation fees from Novo Nordisk, Zylorion, Johnson and Johnson. IK has received speaker fees for non-promotional educational events by Novo Nordisk and Eisai. IK is a paid medical advisor for medical device companies in the dementia field (Five Lives, Prima Mente, Oxford Brain Diagnostics).