Sex-Based Differences in Perioperative Brain Health Outcomes

Topic: Risk, prevention and care in population studies

UNDERLYING BIOLOGICAL MECHANISMS PNDs result from a complex interplay of multiple biological, genetic, and environmental factors (Table 1). Estrogen supports BBB function by upregulating tight junction proteins (claudin-5, occludin), enhancing nitric oxide–mediated vasodilation, and promoting angiogenesis via vascular endothelial growth factor (VEGF) signaling.11–13 Premenopausal women have higher cerebral blood flow than men, which may confer resilience against ischemic and inflammatory insults.11 These neurovascular benefits decrease with menopause: declining estrogen levels are associated with increased BBB permeability, decreased microglial regulation, and heightened neuroinflammatory responses, contributing to greater risk of PND in postmenopausal women.5,11,19 Testosterone also influences BBB integrity in a dose-dependent manner: physiological levels support vascular stability and dampen inflammation, whereas low levels increase permeability and cytokine release, and excessive levels promote vascular inflammation and thrombosis.5,6,13 Neuroinflammatory Cascades Sexual dimorphism is observed in baseline immune profiles. When sex is examined, results are frequently inconsistent or null, often in the context of limited total sample size, marked sex imbalance, or insufficient power to detect sex-by-context interactions. In a 2023 systematic review of 165 studies, only 29 reported sex as a variable in relation to POD, and just five identified sex as a significant risk factor (three female, two male).1 Notably, no pooled meta-analysis of sex effects was performed, underscoring the fragmented nature of the evidence. Cardiac surgery studies yield conflicting results, with some reporting higher POD risk among men26 and others reporting substantially higher risk among women in pooled analyses of randomized trials.27 Orthopedic surgery studies more consistently identify male sex as a risk factor for POD,25,28,30 though these associations often attenuate after adjustment for comorbidities and age. These findings in two different patient populations highlight the ambiguity surrounding the role of sex in perioperative brain health outcomes. Table 2. - Summary of Sex-Based Differences in Perioperative Delirium and Neurocognitive Disorder Outcomes Across Clinical Studies Study—setting Population Sex-based findings Comments Systematic review1 165 studies included: Adults >18 yNoncardiac and non-neurologic surgeries -29 of 165 studies reported data on sex association

@article{seyour2026-42139451,
  author  = {Seyour, Mohamed and Berger‐Estilita, Joana and Gisselbaek, Mia and Rubulotta, Francesca and Saxena, Sarah},
  title   = {{Sex-Based Differences in Perioperative Brain Health Outcomes}},
  journal = {A\&A Practice},
  year    = {2026},
  doi     = {10.1213/xaa.0000000000002200},
  pmid    = {42139451},
  url     = {https://doi.org/10.1213/xaa.0000000000002200}
}

Key findings

• UNDERLYING BIOLOGICAL MECHANISMS PNDs result from a complex interplay of multiple biological, genetic, and environmental factors (Table 1).
• Estrogen supports BBB function by upregulating tight junction proteins (claudin-5, occludin), enhancing nitric oxide–mediated vasodilation, and promoting angiogenesis via vascular endothelial growth factor (VEGF) signaling.11–13 Premenopausal women have higher cerebral blood flow than men, which may confer resilience against ischemic and inflammatory insults.11 These neurovascular benefits decrease with menopause: declining estrogen levels are associated with increased BBB permeability, decreased microglial regulation, and heightened neuroinflammatory responses, contributing to greater risk of PND in postmenopausal women.5,11,19 Testosterone also influences BBB integrity in a dose-dependent manner: physiological levels support vascular stability and dampen inflammation, whereas low levels increase permeability and cytokine release, and excessive levels promote vascular inflammation and thrombosis.5,6,13 Neuroinflammatory Cascades Sexual dimorphism is observed in baseline immune profiles.
• When sex is examined, results are frequently inconsistent or null, often in the context of limited total sample size, marked sex imbalance, or insufficient power to detect sex-by-context interactions.
• In a 2023 systematic review of 165 studies, only 29 reported sex as a variable in relation to POD, and just five identified sex as a significant risk factor (three female, two male).1 Notably, no pooled meta-analysis of sex effects was performed, underscoring the fragmented nature of the evidence.
• Cardiac surgery studies yield conflicting results, with some reporting higher POD risk among men26 and others reporting substantially higher risk among women in pooled analyses of randomized trials.27 Orthopedic surgery studies more consistently identify male sex as a risk factor for POD,25,28,30 though these associations often attenuate after adjustment for comorbidities and age.

Why it matters

This review discusses sex-based differences in perioperative brain health outcomes and notes that when sex is examined, results are frequently inconsistent or null. It does not test or demonstrate any treatment, cure or prevention for Alzheimer's disease.

New to this subject? Start with our plain-English guide: Genetics →

Study details

• Study designsystematic review
• Participants7,900
• Effect sizeOR = 11.02; OR = 5.78; OR = 1.1
• Evidence strengthHigh

Read the original

• DOI: 10.1213/xaa.0000000000002200
• PubMed: 42139451
• Original source →
• Free full text: ORBi UMONS →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Related studies in Risk genes beyond APOE

• Transcriptomic analysis from 3D cultures of Presilinin‐1 G206A carriers reveals genetic expression differences associated with age‐of‐onset variability Alzheimer s & Dementia · 2025-12-01 · usefulness score 39/100
• Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease Human molecular genetics · 1998-01-01 · usefulness score 50/100
• Biological inorganic and bioinorganic chemistry of neurodegeneration based on prion and Alzheimer diseases Dalton transactions (Cambridge, England : 2003) · 2004-05-11 · usefulness score 41/100
• Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based lysine acetyltransferases post-translationally regulate BACE1 levels The Journal of biological chemistry · 2008-11-14 · usefulness score 41/100
• Amyloid beta: structure, biology and structure-based therapeutic development Acta pharmacologica Sinica · 2017-07-17 · usefulness score 38/100
• Developments on BACE 1 Inhibitors as Anti‐Alzheimer Agents: A Perspective on Medicinal Chemistry‐Based Advances Archiv der Pharmazie · 2026-03-01 · usefulness score 33/100

Also in Risk genes beyond APOE

98 studies in the library are filed under Risk genes beyond APOE with no topic tag they share with another; these are this study's neighbours in a fixed tour of them. The Risk genes beyond APOE hub.

• Biochemical markers in persons with preclinical familial Alzheimer disease Neurology · 2008-05-28 · usefulness score 54/100 · Risk genes beyond APOE
• Seizures in dominantly inherited Alzheimer disease Neurology · 2016-07-27 · usefulness score 56/100 · Risk genes beyond APOE
• Platelet activation in Alzheimer disease Archives of neurology · 1998-04-01 · usefulness score 47/100 · Risk genes beyond APOE

Similar studies

• Sexual dimorphism of the developing human brain 1997 · Hippocampus size on brain scans
• Surgery, neuroinflammation and cognitive impairment 2018 · Caregiving
• Postoperative cognitive dysfunction 2014 · Getting a diagnosis
• Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease: A Systematic Review and Meta-analysis 2021 · Treatments
• Postoperative Cognitive Dysfunction and Noncardiac Surgery 2018 · Clinical safety
• Deep brain stimulation: postoperative issues 2006 · Digital health tools

More on Risk genes beyond APOE

• A review that covers this ground The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer's Disease and Other Neurodegenerative Disorders Neurochemical research · 2020-03-13 · usefulness score 47/100
• Newest in this subject Pregnancy History and Loss of Normal PSEN2 Function Impact Female Late-Life Cognitive Processing, Inhibitory Signaling, and Gliosis bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Temporal Proteomics Links the APP London Mutation to Early Cholesterol Remodeling Cell Programs in Human Neurons bioRxiv · 2026-10-24 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Risk genes beyond APOE →