Pregnancy Hypertension and Elevated p-tau217: A Midlife Indicator of Alzheimer’s Disease Risk in Women

Introduction

Pregnancy hypertension, encompassing conditions like gestational hypertension and preeclampsia, affects a significant proportion of women worldwide and has traditionally been viewed in the context of peripartum complications. However, emerging evidence suggests that hypertensive disorders during pregnancy may have long-term implications beyond cardiovascular health. Notably, there is a growing interest in understanding their potential role in neurodegenerative diseases, particularly Alzheimer’s disease (AD). AD, characterized pathologically by amyloid plaques and neurofibrillary tangles composed of hyperphosphorylated tau, often begins insidiously with preclinical or mild cognitive impairment (MCI) stages long before overt dementia. Phosphorylated tau 217 (p-tau217) has recently gained traction as a highly sensitive biomarker reflecting AD pathology. Yet, the interplay between pregnancy hypertension and subsequent AD biomarker profiles in midlife women remains poorly understood. This gap underpins the clinical need for better risk stratification and early detection strategies for women predisposed to AD based on reproductive health history.

Study Design and Methods

This study enrolled 743 cognitively unimpaired, community-dwelling midlife women (mean age 62.9 years, range 50.7–76.6), recruited from well-woman clinics at the National University Hospital in Singapore. Comprehensive sociodemographic information and detailed obstetric history, including pregnancy hypertension episodes, were collected. Cognitive status was screened using the Montreal Cognitive Assessment-Basic (MoCA-B), with a subset identified as having mild cognitive impairment (MCI). Biological measures included fasting blood collection for renal function assessment, APOE genotyping (a key genetic risk factor in AD), and quantification of serum p-tau217 using the high-sensitivity Simoa® ALZpath p-tau217 Advantage PLUS assay. To explore the association between pregnancy hypertension and p-tau217 levels, general linear modeling was employed, controlling for confounders such as age, presence of MCI, BMI, hypertension, renal function, and APOE4 genotype status.

Key Findings

Among the cohort, 9.2% (n=68) reported a history of pregnancy hypertension. The multivariate analysis yielded several independent predictors of elevated serum p-tau217 levels. Increased age and MCI were associated with higher p-tau217, supporting the biomarker’s validity in reflecting neurodegenerative progression. Interestingly, lower BMI and impaired renal function (eGFR <60 mL/min/1.73 m2) were linked to elevated p-tau217, highlighting potential metabolic and systemic contributors to AD pathology. APOE4 genotype carriers, consistent with prior literature, demonstrated significantly raised p-tau217 levels.

Crucially, a history of pregnancy hypertension independently correlated with higher serum p-tau217 levels [mean difference: 0.040 (95% CI: 0.013, 0.067)], even after adjusting for traditional AD risk factors. The magnitude of this association was comparable to that seen in APOE4 carriers, underscoring pregnancy hypertension as a novel, midlife marker of increased AD pathology.

Expert Commentary

This investigation is among the first to link pregnancy hypertension with a validated serum biomarker of AD pathology in asymptomatic midlife women. The findings are biologically plausible given that pregnancy hypertensive disorders have been associated with endothelial dysfunction, chronic inflammation, and cerebrovascular alterations — all factors implicated in AD pathophysiology. Moreover, the study’s adjustment for renal function and cognitive status strengthens the argument that pregnancy hypertension independently contributes to later-life neurodegenerative changes rather than being a surrogate for comorbid conditions.

However, certain limitations warrant consideration. The cross-sectional design precludes causal inference and longitudinal trajectory analysis of p-tau217 in this population. Self-reported pregnancy hypertension may introduce recall bias, although it remains a pragmatic clinical marker. Additionally, the study population was ethnically homogenous (Singaporean women), which may affect generalizability globally.

Future studies would benefit from longitudinal follow-up with neuroimaging correlates and inclusion of diverse populations to validate findings. Understanding mechanistic links, such as the role of vascular changes and inflammation bridging pregnancy hypertension and tau phosphorylation, is another compelling direction.

Clinical Implications and Conclusions

The association between pregnancy hypertension and elevated serum p-tau217 in cognitively healthy midlife women identifies pregnancy hypertension as a potentially valuable clinical indicator for increased AD risk. Given that p-tau217 is a marker of early AD neuropathology, these findings suggest that women with pregnancy hypertensive histories could be prioritized for early biomarker screening and preventive interventions long before cognitive symptoms emerge.

Integrating pregnancy hypertension history into midlife risk assessments could refine personalized approaches to AD screening and management among women. This perspective reinforces the importance of a life-course approach in women’s health, connecting obstetric history with neurodegenerative disease risk.

In summary, this study highlights the need for heightened awareness of pregnancy hypertension’s long-term neurological implications and supports further research into strategies enabling timely AD detection and intervention in at-risk women.