Alzheimer's Biomarker p-tau217 May Identify Women at Higher Dementia Risk from Combined Hormone Therapy
核心洞察
A new study finds that elevated plasma p-tau217 (搜索), an Alzheimer's biomarker, is associated with roughly three times the risk of dementia in older women.
Among women using combined estrogen-progesterone therapy, higher p-tau217 (搜索) levels were linked to approximately four times the dementia risk, while estrogen-only therapy showed no such pattern.
The findings suggest p-tau217 (搜索) screening could help identify women who may be more vulnerable to cognitive decline when starting combined hormone therapy after age 65.
A new analysis from the Women's Health Initiative studies suggests that a blood-based Alzheimer's biomarker could help clinicians determine which women face heightened dementia risk when using certain forms of hormone therapy. The findings, published March 10, 2026 in JAMA Network Open, indicate that plasma phosphorylated tau 217 (p-tau217 (搜索)) levels may serve as a screening tool to guide prescribing decisions for menopausal hormone therapy.
Researchers analyzed blood samples from 2,766 women who entered a clinical trial between 1996 and 1999, tracking participants through 2021 to assess whether baseline plasma p-tau217 (搜索) levels were associated with later dementia and whether that relationship changed based on hormone therapy use.
Biomarker Stratification Reveals Differential Risk
In the study's main analysis, higher baseline p-tau217 (搜索) levels were associated with about three times the risk of developing dementia. However, the relationship diverged sharply depending on the type of hormone therapy administered. Among women assigned to combined estrogen-progesterone therapy, higher biomarker levels were linked to roughly four times the risk of dementia. This pattern was not observed among women using estrogen-only therapy.
The association was strongest in certain subgroups, including women aged over 70, white women, and those carrying the APOE4 (搜索) genotype—a genetic variant known to increase Alzheimer's disease (搜索) risk.
"Importantly, this study does not show that hormone therapy itself causes dementia," the researchers noted. "Instead, it suggests that biological risk markers may help identify women who could be more vulnerable when treatment begins later in life."
Biological Mechanisms Under Investigation
Scientists hypothesize that the difference between therapies may relate to how hormones interact with Alzheimer's pathology. Estrogen may help protect brain cells and influence how the brain processes amyloid and tau proteins that accumulate in Alzheimer's disease (搜索). Progesterone may modify these effects in ways that are not yet fully understood.
The findings align with earlier work showing that carriers of the APOE4 (搜索) genetic risk factor who used hormone therapy also had worse dementia-related biomarkers than those not using hormones or not carrying the genetic risk.
Timing Matters: Age at Initiation
The relationship between hormone therapy and dementia risk appears to depend critically on when treatment begins. The original 2003 Women's Health Initiative Memory Study found that combined hormone therapy roughly doubled dementia risk among women aged 65 and older. The wider trial was stopped early because overall risks, including breast cancer, stroke, and blood clots, outweighed benefits.
However, follow-up analyses of women who started hormone therapy between ages 50 and 54 found no evidence that treatment affected cognitive function when assessed six to seven years after the trial ended. Similar findings have been reported in other clinical trials of relatively healthy women who began hormone therapy close to menopause, suggesting that up to ten years of combined hormone therapy appears generally safe but does not provide measurable cognitive benefits.
Among women who began hormone therapy after age 65, overall cognitive performance declined when tested around age 70, with the decline particularly noticeable in those who already had lower cognitive function at baseline. A 2010 analysis of the same cohort showed trends toward smaller volumes in the hippocampus and frontal lobes among older women using combined hormone therapy—brain changes commonly seen in Alzheimer's disease (搜索).
Clinical Implications
Taking hormone therapy for five years or less when started around menopause has not been linked to increased cognitive decline or Alzheimer's disease (搜索) in clinical trials or in most national registry studies. Because most women use hormone therapy for a limited time to manage menopausal symptoms, it is unlikely to increase dementia risk when started around menopause.
The new analysis is consistent with meta-analyses of national registry data showing increased Alzheimer's risk in older women using combination hormone therapy but not estrogen alone. A smaller increase was also seen in women nearer menopause when treatment lasted more than five years.
The study, titled "Plasma Phosphorylated Tau 217 and Incident Mild Cognitive Impairment and Dementia in Older Women," was led by Aladdin H. Shadyab and colleagues, with senior authors including JoAnn E. Manson and Linda K. McEvoy.