Category: 8. Health

A protein long blamed for the brain damage seen in Alzheimer’s disease has now been found in astonishingly high levels in healthy newborn babies, challenging decades of medical dogma.

The discovery could transform our understanding of both brain development and Alzheimer’s disease itself. The protein, called p-tau217, has been viewed as a hallmark of neurodegeneration – yet a new study reveals it’s even more abundant in the brains of healthy infants.

Rather than being toxic, p-tau217 may be essential for building the brain during early development.

To understand why this matters, it helps to know what tau normally does. In healthy brains, tau is a protein that helps keep brain cells stable and allows them to communicate – essential functions for memory and overall brain function. Think of it like the beams inside a building, supporting brain cells so they can function properly.

But in Alzheimer’s disease, tau gets chemically changed into a different form called p-tau217. Instead of doing its normal job, this altered protein builds up and clumps together inside brain cells, forming tangles that impair cell function and lead to memory loss typical of the disease.

For years, scientists have assumed high levels of p-tau217 always spell trouble. The new research suggests they’ve been wrong.

An international team led by the University of Gothenburg analysed blood samples from over 400 people, including healthy newborns, young adults, elderly adults and those with Alzheimer’s disease. What they found was striking.

Premature babies had the highest concentrations of p-tau217 of anyone tested. Full-term babies came second. The earlier the birth, the higher the protein levels – yet these infants were perfectly healthy.

These levels dropped sharply during the first months of life, remained very low in healthy adults, then rose again in people with Alzheimer’s – though never reaching the sky-high levels seen in newborns.

The pattern suggests p-tau217 plays a crucial role in early brain development, particularly in areas controlling movement and sensation that mature early in life. Rather than causing harm, the protein appears to support the building of new neural networks.

Rethinking Alzheimer’s disease

The implications are profound. First, the findings clarify how to interpret blood tests for p-tau217, recently approved by US regulators to aid dementia diagnosis. High levels don’t always signal disease – in babies, they’re part of normal, healthy brain development.

More intriguingly, the research raises a fundamental question: why can newborn brains safely handle massive amounts of p-tau217 when the same protein wreaks havoc in older adults?

If scientists can unlock this protective mechanism, it could revolutionise Alzheimer’s treatment. Understanding how infant brains manage high tau levels without forming deadly tangles might reveal entirely new therapeutic approaches.

The findings also challenge a cornerstone of Alzheimer’s research. For decades, scientists have believed p-tau217 only increases after another protein, amyloid, starts accumulating in the brain, with amyloid triggering a cascade that leads to tau tangles and dementia.

But newborns have no amyloid buildup, yet their p-tau217 levels dwarf those seen in Alzheimer’s patients. This suggests the proteins operate independently and that other biological processes – not just amyloid – regulate tau throughout life.

The research aligns with earlier animal studies. Research in mice showed tau levels peak in early development then fall sharply, mirroring the human pattern. Similarly, studies of foetal neurons found naturally high p-tau levels that decline with age.

If p-tau217 is vital for normal brain development, something must switch later in life to make it harmful. Understanding what flips this biological switch – from protective to destructive – could point to entirely new ways of preventing or treating Alzheimer’s.

For decades, Alzheimer’s research has focused almost exclusively on the damage caused by abnormal proteins. This study flips that perspective, showing one of these so-called “toxic” proteins may actually play a vital, healthy role at the start of life.

Babies’ brains might hold the blueprint for keeping tau in check. Learning its secrets could help scientists develop better ways to preserve cognitive function as we age, transforming our approach to one of medicine’s greatest challenges.

Rahul Sidhu, PhD Candidate, Neuroscience, University of Sheffield

This article is republished from The Conversation under a Creative Commons license. Read the original article.

New research reveals that oleic acid, abundant in olive oil, protects aging mice from gum infection-induced bone loss and gut microbiome disruption, highlighting how what we eat may help prevent age-related disease.

Study: Mediterranean diet component oleic acid decreases systemic impact of periodontal Porphyromonas gingivalis-infection in age: addressing role of stress resistance and microbiome. Image Credit: Me dia / Shutterstock

In a recent study published in the journal npj Aging, researchers investigated whether dietary intervention alleviates the age-related systemic impact of oral infection with Porphyromonas gingivalis in a mouse model.

Periodontitis is an age-related disease characterized by a hyperinflammatory immune response, systemic inflammation, and shifts in the pathological oral microbiome. Severe periodontal diseases (PDs) affect about 19% of adults worldwide, i.e., over one billion people. PD is a disease of the tissues around the teeth, where plaque and bacterial pathogens accumulate, leading to a heightened inflammatory response and impaired resolution of inflammation.

Comorbidities, such as diabetes, cardiovascular disease, and osteoporosis, can compromise tissue homeostasis at the infection site and lead to increased systemic bone loss. Oleic acid (OA) is a monounsaturated fatty acid, the main component of olive oil and the Mediterranean diet. Serum levels of OA negatively correlate with periodontal tissue loss. In contrast, serum levels of saturated fats, especially palmitic acid (PA), a component of the Western diet, positively correlate with PD.

One study reported that an OA-enriched diet (OA-ED) in mice with periodontal infection improved femoral bone microarchitecture and reduced systemic inflammation and alveolar bone loss compared to mice on a PA-enriched diet (PA-ED). Further, a diet rich in saturated fats is associated with PD progression in older individuals. However, whether aged individuals could benefit from specific nutritional components is unknown.

The study and findings

In the present study, researchers investigated whether nutritional interventions with OA could modulate responses to periodontal infection and protect against systemic effects associated with aging. First, young (five-week-old) and old mice (at least 73 weeks old) were fed a PA-ED, OA-ED, or normal diet (ND) for 16 weeks. Following five weeks of oral P. gingivalis inoculation, alveolar bone crest height was unchanged in young mice.

In contrast, the distance between the alveolar bone crest and the cemento-enamel junction increased by 63% in infected, old mice fed PA-ED compared to their aged OA-ED counterparts. Infection increased bone loss around the periodontal ligament (PDL) in old and young mice on PA-ED compared to those on OA-ED or ND. Furthermore, bone loss in PDL was accompanied by increased osteoclasts in aged, infected mice on PA-ED relative to their aged, OA-ED counterparts.

Next, microbial composition was analyzed in fecal samples one week and eight weeks after diet initiation. After one week, a distinct microbial pattern was observed in PA-ED-fed mice, characterized by increased Lachnospiraceae subtypes and reduced relative abundances of Muribaculaceae and Akkermansia. In contrast, the microbial composition was comparable between old and young mice on ND and OA-ED during the first eight weeks.

Further, mice were treated with an oral antibiotic (enrofloxacin) to evaluate whether dietary intake could modulate microbiome resilience in both age groups. The microbiome of old and young PA-ED-fed animals showed marked changes in taxonomic composition with antibiotic treatment. On the other hand, OA-ED-fed mice, especially young animals, had minor changes in taxonomic composition after antibiotic exposure.

Notably, while the microbiome of animals on ND or OA-ED returned to their pre-antibiosis state during the six-week follow-up, PA-ED-fed mice failed to recover their microbiome from antibiotic-induced shifts. The article notes that P. gingivalis itself was not detected in the gut, indicating that the observed microbiome effects were indirect. Further, the team performed a systemic serum analysis of stress resilience phospholipid indicators to investigate whether OA-ED supports stress response and resilience associated with age and P. gingivalis infection.

PA-ED mice differed in their serum phosphatidylinositol (PI) composition compared to ND and OA-ED mice. Uninfected ND and OA-ED animals showed age-related differences in PI proportions. Conversely, the PI proportion in uninfected PA-ED animals was comparable between old and young animals. However, P. gingivalis infection of old PA-ED-fed mice induced the most pronounced changes in lipidomic composition.

In contrast, infection of old OA-ED or ND mice did not induce marked changes in PI composition relative to their younger counterparts. PA-ED resulted in lower serum levels of the stress-reducing lipokine, PI(18:1/18:1), in both age groups compared to ND or OA-ED. PI(18:1/18:1) is linked to stress resistance, autophagy, and ERK1/2 modulation; however, the precise mechanisms underlying these associations remain under investigation. Moreover, P. gingivalis infection further reduced PI(18:1/18:1) levels in old and young PA-ED-fed mice and young ND-fed mice. By contrast, OA-ED stabilized PI(18:1/18:1) levels in infected young and old mice.

Additional experiments indicated that PA-ED increased osteoclast differentiation and primed bone marrow cells to inflammation, while OA-ED alleviated these effects. Furthermore, osteoblasts showed baseline inflammation and reduced responsiveness to infection in aged mice, promoting a pro-inflammatory microenvironment. PA-ED also increased femoral bone loss in response to infection in old mice.

The study design used only male mice to control for hormonal influences on bone metabolism; this limitation is important for interpreting and translating the results to both sexes. The authors also note that, while the study reveals strong mechanistic associations, further research is required to confirm these findings in humans.

Conclusions

The findings reveal that PA-ED aggravated P. gingivalis-related oral bone loss, especially in aged mice. Systemically, PA-ED destabilized the gut microbiota, elevating susceptibility to disturbances and infection-driven microbial shifts. PA-ED also decreased stress resistance and promoted cellular priming, enhancing osteoclast differentiation in infected mice of both age groups.

Osteoblasts showed baseline age-associated inflammation and reduced responses to infectious stimuli, promoting a pro-inflammatory microenvironment. This was accompanied by increased infection-induced femoral bone loss in old mice on PA-ED. Overall, the results suggest OA-ED is protective by limiting PD-associated systemic and local tissue damage with age. These results are based on preclinical animal models, and their applicability to human disease requires further investigation.

New research reveals that vaccines enhanced with the AS01 adjuvant may help shield the aging brain from dementia, potentially redefining vaccine benefits beyond infectious disease protection.

Study: Lower risk of dementia with AS01-adjuvanted vaccination against shingles and respiratory syncytial virus infections. Image Credit: ahmetmapush / Shutterstock

In a recent study in npj Vaccines, researchers demonstrated the short-term (18-month) protective effects of the AS01 adjuvant against the risk of subsequent dementia. This retrospective research leveraged electronic health record data (EHR) from the TriNetX US Collaborative Network, comprising more than 436,000 US adults, approximately half of whom were administered an AS01-adjuvanted vaccine, while the rest received a comparable non-AS01-adjuvanted flu vaccine.

Study findings revealed that participants administered AS01-adjuvanted vaccines (Shingrix or Arexvy) were at a significantly lower risk of dementia over the following 18 months than participants who received the flu vaccine. This result remained robust, irrespective of vaccine type or participant sex, suggesting that the protective effects may be attributed mainly to the adjuvant (AS01) and its potential neuroprotective immune responses. These findings open a new frontier in preventive neurology, potentially positioning AS01-adjuvanted vaccines as promising candidates for delaying or preventing dementia.

Background

Dementia is an umbrella term for several age-associated progressive cognitive declines that can severely hamper daily activities. Dementia represents a global public health concern, estimated to impact more than 57 million people (2021), most of whom are women. In today’s aging world, dementia prevalence continues to rise, with projections suggesting that 139 million adults will have dementia by 2050.

Unfortunately, dementia remains without a cure, with current research efforts focused on identifying its risk factors and developing effective preventive interventions. In light of this, the current research group made an intriguing discovery in their previous work: Shingrix, a shingles vaccine, was associated with a lower risk of dementia compared to live anti-varicella-zoster virus vaccines.

Researchers hypothesized that this either meant that shingles was linked to dementia, or AS01, an adjuvant added to Shingrix to improve its efficacy (no AS01 in live vaccines), was contributing to the observed reduced dementia risk. However, these findings were observational, which raises questions about whether this benefit was derived from better viral protection (against shingles or the varicella-zoster virus) or from interactions between the immune-boosting agents.

About the study

In the present study, researchers sought to isolate the effects of potential shingles-dementia associations by explicitly investigating if AS01 can alter the short-term risk of dementia diagnosis. To do this, they compared individuals who received AS01-adjuvanted vaccines with controls who received a flu vaccine devoid of AS01.

The study compared the relative risk of dementia diagnosis among members of each cohort over the subsequent 18 months. Participant data was obtained from the United States (US) TriNetX Collaborative Network. The electronic health record (EHR) dataset comprised 436,788 US adults (60+ yrs; majority between 70-73) who were administered Shingrix (n = 103,798), Arexvy (another AS01-adjuvanted RSV vaccine; n = 35,938), or a non-AS01-adjuvanted vaccine against the common flu.

Notably, the controls were sociodemographically and medically matched (66 variables) to cases via propensity score matching. Outcomes of interest included positive dementia diagnoses (International Classification of Diseases [ICD-10] codes) within the 18 months following study enrolment/vaccine administration.

Statistical analyses included the Kaplan-Meier estimator for calculating incidences of outcomes, the generalised Schoenfeld approach for assumption testing, and clinically meaningful estimations using a restricted mean time lost (RMTL) model. The primary statistical comparisons were between these vaccine-defined cohorts, and analyses were also stratified by sex.

Study findings

The study demonstrated several compelling findings. First, AS01-adjuvanted vaccines showed impressive short-term (18 months) protective effects against the risk of dementia. Participants who received Arexvy showed a 29% lower risk of dementia compared to controls, while those who received Shingrix showed an 18% reduction. Those who received both vaccines saw a 37% lower risk.

Notably, the protective impacts of these vaccines were statistically indistinguishable, strengthening support that the AS01 adjuvant, the only commonality between the vaccines, is a plausible explanation for the observed protective effect. Independent laboratory studies bolster this idea, though the paper’s authors note that the exact mechanisms remain speculative. They highlight that AS01 activates innate immune cells, such as microglia, thereby enhancing pathogen clearance and reducing inflammation processes implicated in Alzheimer’s disease and the risk and progression of dementia.

Interestingly, the authors report a key limitation that may mean the protective effect is even stronger than observed. The RSV vaccine group likely included some patients who received a non-AS01 vaccine, suggesting the true impact of the AS01-adjuvanted vaccine (Arexvy) may be underestimated.

In contrast, the hypothesized anti-viral benefits of these vaccines on dementia risk (and by extension, the potential associations between the diseases and dementia) remain unlikely. These results remained robust following sensitivity testing and adjustments for vaccine type and sex. However, the authors stress that, because the study is observational, it reveals that unmeasured confounding factors may influence an association rather than a proven causal link, and the findings.

A. Association between AS01-adjuvanted vaccines and risk of dementia, negative control outcome, and zoster infection. Each dot and bold number represent the ratio of restricted mean time lost (RMTL) for the comparison between two cohorts, while horizontal lines and numbers in brackets are 95% confidence intervals. RMTL ratios below 1 indicate that the risk is lower in the first cohort (e.g., recipients of the RSV vaccine on the first line) than in the second (e.g., recipients of the flu vaccine). B. Associations between AS01-adjuvanted vaccines (compared to flu vaccine) and risk of dementia in females, males, and in the cohorts including people who developed dementia within the first 3 months post-vaccination.

Conclusions

This real-world study contributes to the growing body of evidence that AS01-adjuvanted vaccines may protect brain health beyond their intended viral targets. With both RSV and shingles vaccines showing significant dementia risk reduction (29% for RSV and 18% for shingles), their shared efficacy, rather than specific disease prevention, appears key to their holistic dementia-preventive effects.

The findings strongly support the need for future randomized clinical trials to confirm these effects and test AS01 boosters for the prevention of dementia. If confirmed, we may be able to harness vaccine platforms not just for infectious disease control, but as tools to delay or prevent cognitive decline, thereby representing a significant paradigm shift in preventive geriatrics.

Newswise — Childhood obesity may be caused by more than poor diet and insufficient physical activity. The latest research suggests that at least some of the risk for obesity may originate in the womb, where the fetus is exposed to the mother’s metabolic state, including her blood sugar levels.

This is called “metabolic programming.” When maternal blood sugar is high during pregnancy, children tend to have higher rates of obesity and disordered glucose metabolism. They may have higher body fat in infancy, then childhood and eventually in adulthood. But could this trajectory be altered?

Researchers at Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues are now turning their attention to breastfeeding as the next critical stage of metabolic programming. They are investigating how blood sugar levels in pregnancy affect nutrient composition of breast milk, focusing on fatty acids known to regulate offspring body fat. They also are trying to determine the impact on the child’s weight and body fat, accounting for the child’s diet.

“We are studying the influence of maternal metabolism during pregnancy on both breast milk composition and the child’s metabolism,” said Co-Principal Investigator Jami Josefson, MD, pediatric endocrinologist and scientist at Lurie Children’s, the lead site for the study. “We are considering the entire range of blood sugar levels during pregnancy, from normal to gestational diabetes.”

Since October 2023, the study enrolled 180 mother/baby pairs, with the goal of enrolling 400. All the mothers in this study were participants in another study that collected detailed metabolic data throughout their pregnancy. These data will be linked to their breast milk composition profiles, as well as body fat measurements of the mother and baby at 1 month, 2 months, 6 months and 2 years of age.

“We hope to advance understanding of how in utero exposures modify lactational programming,” said Dr. Josefson. “Ultimately, our goal is to identify interventions to mitigate adverse developmental programming and prevent childhood obesity.”

The Glycemia Range and Offspring Weight and adiposity in response To Human milk (GROWTH) study is funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Dr. Josefson is the Children’s Research Fund Junior Board Research Scholar at Stanley Manne Children’s Research Institute at Lurie Children’s. She also is Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine.

Daniel Robinson, MD, neonatologist and scientist at Lurie Children’s, is the Co-Principal Investigator on the GROWTH study. He is the Founders’ Board Neonatology Young Research Scholar at Manne Research Institute and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine.

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(Boston)—While severe maternal hypothyroidism (low thyroid hormone levels) in pregnancy is known to increase risks of adverse pregnancy outcomes, it is unclear whether mild (subclinical) hypothyroidism causes similarly adverse pregnancy complications. It is also not clear whether maternal hypothyroidism in pregnancy increases risks of gestational diabetes.

A new study in the journal Lancet Diabetes and Endocrinology (Osinga et al “Association of gestational thyroid function and thyroid autoimmunity with gestational diabetes mellitus: a systematic review and individual-participant meta-analysis”) investigated a potential association between maternal thyroid function in pregnancy and risk of gestational diabetes. The study, which used data from a large sample of patients from several different studies, found low free thyroxine (FT4) levels in pregnancy was associated with increased risk of gestational diabetes (6.5% vs 3.5% in those with normal FT4 levels). However, patients with mild subclinical hypothyroidism (high thyrotropin, or TSH, and normal FT4 level) were not at increased risk of gestational diabetes.

“Since TSH is used as the screening test for thyroid dysfunction, it is unclear whether these new findings should change the current practice of thyroid function screening in pregnancy,” says Sun Young Lee MD, MSc, assistant professor of medicine at Boston University Chobanian & Avedisian School of Medicine in an accompanying commentary, (https://www.thelancet.com/journals/landia/article/PIIS2213-8587(25)00126-3/fulltext). “Currently available laboratory tests can also result in falsely low FT4 levels in pregnancy because of interference from normal changes in protein levels in pregnancy,” adds Lee who also is an endocrinologist at Boston Medical Center.

Presently, routinely checking thyroid hormone levels in pregnancy is not recommended. In her commentary, Lee points out that other clinical trials have not shown that treatment of mild maternal hypothyroidism in pregnancy decreases risks of pregnancy complications. “It is unclear whether the findings of this study would advocate for universal screening and treatment of mild subclinical maternal hypothyroidism.”

Lee believes further clinical trials are needed to study the potential benefit of levothyroxine treatment of low FT4 levels in pregnancy in decreasing risks of pregnancy. In the meantime, she feels more vigilant screening of gestational diabetes in patients with known thyroid disease is important.

Newswise — Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, known for its aggressive behavior and resistance to treatment. Treating PDAC is challenging because the tumors are extraordinarily complex, with a chaotic mix of cells with different behaviors, vulnerabilities, and gene expression patterns.

In a study published in Nature Genetics, researchers from the University of Chicago developed a powerful statistical method called Generalized Binary Covariance Decomposition (GBCD) to better understand this complexity. This method enables researchers to analyze massive single-cell RNA sequencing datasets and uncover recurring patterns of gene activity across diverse patient tumors.

By applying GBCD to thousands of individual cancer cells from multiple studies, the team discovered previously hidden gene expression programs, particularly a stress-response signature that is linked to poor survival outcomes. This new method could be a powerful tool for identifying high-risk patients and developing more personalized treatment strategies.

Understanding tumors’ mixed make-up through variations in gene expression

Genetic and epigenetic alterations are major drivers of fatal diseases like cancer. These alterations impact cellular function by changing gene expression and leading to transcriptional heterogeneity—a phenomenon in which patterns of gene activity differ across cells. Every tumor contains a complicated mix of cell types and states. Some cells grow rapidly, others remain dormant; Some respond to drugs, others are resistant to treatment.

“A big question in cancer is, how does gene expression predict or causally impact the way a tumor develops or how patients respond to therapy?” said senior author Matthew Stephens, PhD, FRS, Professor and Chair of the Department of Statistics and Professor of Human Genetics at UChicago. “If we understood how transcriptional variation predicts prognosis and therapy response, then we could improve therapies because transcriptional variation is relatively easy to measure.”

Sometimes it is not just a single gene, but a set of genes that exhibit coordinated transcriptional changes. These are known as gene expression programs, which can characterize cancer molecular subtypes, influence tumor progression, and affect therapy response.

Revealing layers within tumor complexity

Historically, most transcriptomic data came from bulk RNA sequencing, which measures gene expression in a group of cells rather than in individual cells. The issue with bulk transcriptomic data is that it provides measurement at the patient level. In contrast, single-cell RNA sequencing (scRNA-seq) data measures gene expression at single-cell resolution, revealing transcriptional heterogeneity among cells from the same patient.

Modern technologies like scRNA-seq allow researchers to measure the activity of thousands of genes in individual cancer cells, offering much higher resolution of the transcriptional heterogeneity within tumors. However, the resulting massive datasets pose a challenge: distinguishing meaningful signals from noise.

In the current study, the team focused on analyzing transcriptional variation using scRNA-seq data. “Studying single-cell data allows us to see much more structure than what we can observe with bulk RNA-seq,” said Yusha Liu, PhD, a former postdoctoral researcher in the Stephens lab who led the study. Unified analysis of scRNA-seq data from multiple studies and patients can identify recurrent patterns of transcriptional variation related to cancer etiology, such as molecular subtypes. There may also be other biological activities or cellular processes occurring in tumor cells that aren’t directly tied to known molecular subtypes but still have significant implications for patient outcomes.

“Although tumor subtype identification is helpful in guiding treatment choices, the molecular landscape is very complex,” Stephens said. “We are trying to identify gene expression programs using Generalized Binary Covariance Decomposition (GBCD), a statistical method designed to analyze transcriptional heterogeneity in single-cell RNA data and detect patterns beyond known subtypes.” This method allows researchers to break down the complex variation in gene activity into distinct, interpretable components.

Stress response signature offers clues to pancreatic cancer survival

To test the new GBCD method, researchers analyzed 35,000 cancer cells from 59 patients with PDAC. GBCD not only identified the well-known “classical” and “basal” PDAC subtypes but also uncovered a previously underappreciated stress-response program strongly associated with poor survival.

They found that many critical genes in this stress-response program are regulated by ATF4, a key transcription factor involved in the “integrated stress response,” a survival mechanism exploited by cancer cells under harsh conditions. Importantly, this stress program predicted worse outcomes in cancer patients independent of tumor stage or known subtype. Identifying this signature could help explain PDAC’s aggressive nature and inform treatment strategies.

“The benefit of our approach is that we can perform a unified or integrative analysis of single-cell RNA-seq data from multiple samples across studies,” Liu said. “This greatly increases the number of patient samples and cells, enhancing our power to identify shared transcriptional patterns. The challenge, however, is the high degree of variability between patients, which can mask these subtle shared patterns and that is what GBCD is designed to tackle.”

According to researchers, the GBCD approach offers a deeper characterization of the transcriptional landscape in pancreatic cancer and could be applied to other cancer types. They hope the tool will advance understanding of cancer biology and etiology, while offering valuable insights to study tumor progression and metastasis.

The study “Dissecting tumor transcriptional heterogeneity from single-cell RNA-seq data by generalized binary covariance decomposition” was supported by grants from the National Institutes of Health, the University of Chicago Medicine Comprehensive Cancer Center, the Leona M. and Harry B. Helmsley Charitable Trust, the Neuroendocrine Tumor Research Foundation, an Ullman Family Dream Team Award, and the Government of Ontario.

Additional authors included Scott A. Oakes and Kay F. Macleod from the University of Chicago, and Jason Willwerscheid from Providence College, RI.

Scientists at the National Institutes of Health (NIH) have found that two common types of hormone therapy may alter breast cancer risk in women before age 55. Researchers discovered that women treated with unopposed estrogen hormone therapy (E-HT) were less likely to develop the disease than those who did not use hormone therapy. They also found that women treated with estrogen plus progestin hormone therapy (EP-HT) were more likely to develop breast cancer than women who did not use hormone therapy. Together, these results could help to guide clinical recommendations for hormone therapy use among younger women.

The two hormone therapies analyzed in the study are often used to manage symptoms related to menopause or following hysterectomy (removal of uterus) or oophorectomy (removal of one or both ovaries). Unopposed estrogen therapy is recommended only for women who have had a hysterectomy because of its known association with uterine cancer risk.

“Hormone therapy can greatly improve the quality of life for women experiencing severe menopausal symptoms or those who have had surgeries that affect their hormone levels,” said lead author Katie O’Brien, Ph.D., of NIH’s National Institute of Environmental Health Sciences (NIEHS). “Our study provides greater understanding of the risks associated with different types of hormone therapy, which we hope will help patients and their doctors develop more informed treatment plans.”

The researchers conducted a large-scale analysis that included data from more than 459,000 women under 55 years old across North America, Europe, Asia, and Australia. Women who used E-HT had a 14% reduction in breast cancer incidence compared to those who never used hormone therapy. Notably, this protective effect was more pronounced in women who started E-HT at younger ages or who used it longer. In contrast, women using EP-HT experienced a 10% higher rate of breast cancer compared to non-users, with an 18% higher rate seen among women using EP-HT for more than two years relative to those who never used the therapy.

According to the authors, this suggests that for EP-HT users, the cumulative risk of breast cancer before age 55 could be about 4.5%, compared with a 4.1% risk for women who never used hormone therapy and a 3.6% risk for those who used E-HT. Further, the association between EP-HT and breast cancer was particularly elevated among women who had not undergone hysterectomy or oophorectomy. That highlights the importance of considering gynecological surgery status when evaluating the risks of starting hormone therapy, the researchers noted.

“These findings underscore the need for personalized medical advice when considering hormone therapy,” said NIEHS scientist and senior author Dale Sandler, Ph.D. “Women and their health care providers should weigh the benefits of symptom relief against the potential risks associated with hormone therapy, especially EP-HT. For women with an intact uterus and ovaries, the increased risk of breast cancer with EP-HT should prompt careful deliberation.”

The authors noted that their study is consistent with previous large studies that documented similar associations between hormone therapy and breast cancer risk among older and postmenopausal women. This new study extends those findings to younger women, providing essential evidence to help guide decision-making for women as they go through menopause.

Reference: O’Brien KM, et al. 2025. Hormone therapy use and young-onset breast cancer: a pooled analysis of prospective cohorts included in the Premenopausal Breast Cancer Collaborative Group. Lancet Oncol 26: 911–23.