The progression of sex differences in brain networks across the lifespan

bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-31 · 1 citations

Sex differences in brain connectivity are well documented, yet how these differences evolve across the human lifespan remains poorly understood. Rigorously assessing sex-dependent trajectories of brain network organization is challenging due to difficulty in acquiring, processing, and modeling high-dimensional connectomes. Here, we analyzed 15 types of functional and structural connectivity networks from 1286 healthy individuals aged 8-100+ years, using our new AI-based Krakencoder to derive a low-dimensional multimodal "fusion" connectome representation. Sex differences were minimal in early childhood, pronounced in young to mid-adulthood, and diverged across modalities in later life: functional connectivity grew less distinct and structural connectivity grew more distinct from midlife onward. Functional differences were driven predominantly by higher-order association networks (default mode, control), while structural differences concentrated in lower-order cerebellar and subcortical pathways. These findings provide a lifespan-wide, multimodal map of sex differences in brain networks which may help inform sex-specific vulnerability and resilience to brain disorders.

Neurobiological Signatures of Endometriosis: Characterizing Pain, Cognition, and Brain Morphology

bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-06

Endometriosis affects approximately 10% of reproductive-age women worldwide and is associated with substantial pain and mental health burden, yet its neurobiological correlates remain poorly characterized. Neuroimaging studies of endometriosis are particularly limited. Here we present a comprehensive, multidimensional investigation of the neurobiology of endometriosis, integrating structural and diffusion neuroimaging, biofluid measures, neuropsychological testing, and detailed health and psychosocial phenotyping in individuals with and without endometriosis. Compared with controls, individuals with endometriosis exhibited higher levels of pain, depression, and anxiety and performed worse across multiple cognitive domains. Global and regional brain morphometric measures did not differ between groups; however, endometriosis-specific pain was associated with altered gray matter volume and white matter microstructure across distributed pain-related neural circuits. These findings identify pain-related neurobiological signatures of endometriosis and establish a foundation for mechanistic and translational studies of its central nervous system effects.

Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer’s disease risk

medRxiv · 2026-02-11

Abstract Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts ( N >3,000) to identify biological changes underlying menopause and its links to brain aging. In N =80 rigorously-phenotyped pre-, peri-, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimer’s disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women ( N =94; N =100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age-matched pre- and postmenopausal women with plasma Olink proteomics ( N =2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and catabolic processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.

Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer’s disease risk

Research Square · 2026-02-12

The Maternal Brain in Context: Systemic Physiological Changes Across Pregnancy

Annual Review of Neuroscience · 2026-04-02

During pregnancy, the maternal body undergoes profound, coordinated physiological adaptations to support the developing fetus, including major shifts in immune regulation and dramatic changes in the vascular system. Accompanying these peripheral adaptations, recent longitudinal studies in humans point to significant remodeling of the nervous system, occurring in lockstep with increases in gonadal hormone production. To understand the neural adaptations tied to pregnancy and the postpartum period, a holistic approach is essential-one that accounts for changes across multiple peripheral systems. In this review, we consider the impact of the endocrine, cardiovascular, microbiome, and immune systems on the maternal brain. By adopting this integrative approach, we aim to better understand the biological pathways that shape the maternal brain during normative pregnancies and those marked by adverse events.

Menarche onset is an inflection point for mental health and brain development

bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-14

Menarche is a normative milestone of female puberty, yet its role in adolescent mental health and brain development remains poorly understood. Using longitudinal data from 5,016 females (7 annual visits, ages 10-16 years) in the Adolescent Brain Cognitive Development Study, we found that menarche onset functions as an inflection point for the development of internalizing symptoms and gross brain morphometry. The onset of menarche, largely independent of timing and socio-environmental factors, preceded a significant spike in internalizing symptoms, while altering the rate of ongoing structural brain development. Following menarche onset, individuals with faster declines in gray matter volume and surface area also had heightened internalizing symptoms. These findings suggest that menarche is not only a reproductive milestone but a neuroendocrine driver of adolescent brain and mental health trajectories. This normative and easily identifiable marker could define a critical window for mental health screenings with greater precision than current age-based guidelines.

Dense sampling for mapping pituitary growth dynamics before, during, and after pregnancy

Journal of Neuroendocrinology · 2026-02-01

Abstract Pregnancy represents a period of profound endocrine activity and neural reorganization. While recent evidence highlights pituitary volume as a biomarker of endocrine dynamics during pregnancy, its precise trajectory (timing and relative magnitude of effect) across human pregnancy remains undescribed. Three healthy women (59 total observations) underwent T1 ‐weighted MRI before conception (5 baseline observations), during pregnancy (38 total observations, spanning gestational weeks 1–36), and up to 1 year postpartum (16 total observations). Anterior and posterior pituitary lobes were manually delineated at every visit. A longitudinal pipeline co‐registered each scan to all other intra‐subject scans, propagated their labels, and generated majority‐vote ensembles for objective and regularized volume estimates. Person‐centered z‐scores were computed, and generalized additive mixed models ( GAMMs ) with random intercepts estimated nonlinear volume trajectories. The anterior lobe followed a nonlinear trajectory, with gestational age explaining 73% of adjusted variance in anterior‐pituitary volume (edf = 7.59, F = 20.2, p bonf < 10 −10 ). Specifically, volume exhibited a modest first trimester decrease (local fit minima: −0.9 SD at 10.6 weeks), followed by a steep rise into the 3rd trimester (local fit maxima: +1.8 SD at 34.1 weeks, or ~ 17.5% increase from 1st trimester minima, by volume), before returning to baseline near 3 months postpartum. Sensitivity analyses restricted to linear regression during early (−5 to 12 weeks) and late (12 to 40 weeks) windows replicated the observed non‐linear decreasing/increasing slopes (β early = −0.09 SD /week, p early = 0.036; β late = 0.14 SD /week, p late < 10 −10 ). In contrast, no significant volumetric changes in the posterior lobe were detected across the observation period (p non‐linear = 0.79). In one of the first studies of its kind to leverage a dense sampling approach in multiple pregnant women, non‐linear analyses revealed rapid, reversible anterior pituitary hypertrophy across human pregnancy consistent with lactotrope expansion and heightened endocrine load.

Plasma proteomics link menopause timing to brain aging and dementia risk

medRxiv · 2026-04-24

Abstract Earlier menopause is a risk factor for several age-related diseases, including dementia. The biological pathways linking menopause timing to later-life brain aging are not understood. Leveraging large-scale plasma proteomics in postmenopausal women from the UK Biobank ( N =15,012), earlier menopause was associated with upregulation of pro-inflammatory and extracellular matrix degradation pathways, plus accelerated aging across proteomic clocks of organ and cellular aging, including brain and oligodendrocyte aging. Elevated GDF15, a canonical aging marker, was the top protein correlate of earlier menopause. We observed robust replication of menopause timing proteomic shifts in the Women’s Health Initiative Long Life Study ( N =1,210). In UKB, proteins associated with earlier menopause, including GDF15, exhibited concordant associations with incident dementia risk and brain atrophy, cerebral small vessel disease burden, and white matter microstructural integrity. Collectively, our findings identify proteomic signatures linking ovarian aging to brain aging, providing a framework to inform interventions to reduce dementia risk.

Author response: Menopausal hormone therapy and the female brain: leveraging neuroimaging and prescription registry data from the UK Biobank cohort

2025-04-01

Menopausal hormone therapy (MHT) is generally thought to be neuroprotective, yet results have been inconsistent. Here, we present a comprehensive study of MHT use and brain characteristics in middle-to older aged females from the UK Biobank, assessing detailed MHT data, APOE ε4 genotype, and tissue-specific gray (GM) and white matter (WM) brain age gap (BAG), as well as hippocampal and white matter hyperintensity (WMH) volumes.A total of 19,846 females with magnetic resonance imaging data were included (current-users = 1,153, 60.1 ± 6.8 years; past-users = 6,681, 67.5 ± 6.2 years; never-users = 12,012, mean age 61.6 ± 7.1 years). For a sub-sample (n = 538), MHT prescription data was extracted from primary care records. Brain measures were derived from T1-, T2- and diffusion-weighted images. We fitted regression models to test for associations between the brain measures and MHT variables including user status, age at initiation, dosage and duration, formulation, route of administration, and type (i.e., bioidentical vs synthetic), as well as active ingredient (e.g., estradiol hemihydrate). We further tested for differences in brain measures among MHT users with and without a history of hysterectomy ± bilateral oophorectomy and examined associations by APOE ε4 status.We found significantly higher GM and WM BAG (i.e., older brain age relative to chronological age) as well as smaller left and right hippocampus volumes in current MHT users, not past users, compared to never-users. Effects were modest, with the largest effect size indicating a group difference of 0.77 years (∼9 months) for GM BAG. Among MHT users, we found no significant associations between age at MHT initiation and brain measures. Longer duration of use and older age at last use post menopause was associated with higher GM and WM BAG, larger WMH volume, and smaller left and right hippocampal volumes. MHT users with a history of hysterectomy ± bilateral oophorectomy showed lower GM BAG relative to MHT users without such history. Although we found smaller hippocampus volumes in carriers of two APOE ε4 alleles compared to non-carriers, we found no interactions with MHT variables. In the sub-sample with prescription data, we found no significant associations between detailed MHT variables and brain measures after adjusting for multiple comparisons.Our results indicate that population-level associations between MHT use, and female brain health might vary depending on duration of use and past surgical history. Future research is crucial to establish causality, dissect interactions between menopause-related neurological changes and MHT use, and determine individual-level implications to advance precision medicine in female health care.

Hormonal milieu influences whole-brain structural dynamics across the menstrual cycle using dense sampling in multiple individuals

Nature Neuroscience · 2025-09-26 · 5 citations

Gonadal hormone receptors are widely distributed across the brain, yet their influence on brain structure remains understudied. Here, using precision imaging, we examined four females, including one with endometriosis and one using oral contraceptives (OC), across a monthly period. Whole-brain analyses revealed spatiotemporal patterns of brain volume changes, with substantial variations across the monthly period. In typical cycles, spatiotemporal patterns were associated with serum progesterone levels, while in cycles with endometriosis and during OC intake, patterns were associated with serum estradiol levels. The volume changes were widely distributed rather than region-specific, suggesting a widespread but coordinated influence of hormonal fluctuations. These findings underscore the importance of considering diverse hormonal milieus beyond typical menstrual cycles in understanding structural brain dynamics and suggest that hormonal rhythms may drive widespread structural brain changes.