This study investigates whether intermittent hypoxia (IH) and physical activity (PA), either alone or in combination (simultaneously or sequentially), can improve cognitive function and brain health in middle-aged adults (50-65 years old). The hypothesis is that (1) each intervention alone (IHT or PA) provides cognitive benefits and (2) combining IHT with PA may yield additive or synergistic effects, particularly when administered simultaneously rather than sequentially. By comparing these distinct interventions, the study aims to determine which approach best preserves or enhances cognitive performance in middle-aged adults. Findings from this research may inform non-pharmacological strategies to promote healthy aging and reduce the risk of age-related cognitive decline.

Rapid demographic aging worldwide is driving a surge in age-related conditions, including neurodegenerative diseases and cognitive disorders. Projections estimate that the number of people living with dementia could reach 78 million by 2030 and 139 million by 2050, underscoring the urgent need for effective, non-pharmacological strategies to preserve brain health. Intermittent hypoxia (IH) and physical activity (PA) are two promising interventions that may help prevent or mitigate cognitive decline. IH-an approach involving repeated cycles of reduced oxygen (11-16% FiO₂) followed by normoxic recovery-has shown benefits across diverse health domains (cardiovascular, metabolic, respiratory, and neurological), potentially through mechanisms such as the activation of Hypoxia-Inducible Factor (HIF), enhanced vascular endothelial growth factor (VEGF) production, and anti-apoptotic pathways. PA is widely recognized for its positive impact on overall health, including cognitive function and neuroplasticity.

The primary objective of this study is to evaluate the effects of IH and PA-administered individually, sequentially, or simultaneously-on cognitive performance and brain health in adults aged 50 to 65. The study will determine whether combining these interventions produces additive or synergistic benefits beyond those observed with each intervention alone. A total of approximately 176 participants will be enrolled and randomly assigned to one of five groups: (1) PA only, (2) IH only, (3) PA + IH sequentially, (4) PA + IH simultaneously, or (5) a control group receiving "placebo" hypoxia. Each participant will complete 18 sessions over a 6-week period (3 sessions per week), with sessions conducted in a hypoxic chamber at CIC 1402 and at the exercise testing facility of the University of Poitiers.

Outcome measures include comprehensive cognitive testing (global cognition, reaction time, executive function, and divided attention), assessments of autonomy (e.g., activities of daily living), and physiological parameters (e.g., SpO₂, cerebral oxygenation, heart rate, and blood pressure). Biomarker analysis will include brain-derived neurotrophic factor (BDNF), VEGF, irisin, and markers of HIF activation to elucidate the mechanisms underlying any observed improvements. Vascular function will be assessed using Doppler ultrasound and near-infrared spectroscopy (NIRS), and daily activity levels will be monitored with accelerometers.

Inclusion criteria require participants to be 50-65 years old, with a Montreal Cognitive Assessment (MoCA) score ≥24, no participation in other exercise interventions in the past 6 months, and no altitude exposure above 1,500 m in the preceding 3 months. Additional eligibility requirements include the absence of chronic kidney, cardiovascular, metabolic, neurological, or orthopedic disease, as well as no significant respiratory history. Exclusion criteria include active smoking, major cardiovascular complications within the last 3 months, severe hypertension, chronic respiratory insufficiency, diabetes, or any other condition that could compromise safety or study compliance. A qualified medical doctor will confirm eligibility during the inclusion process.

By evaluating different delivery methods of IH and PA, this research aims to identify the most effective, non-pharmacological approach to preserving-or potentially enhancing-cognitive function in middle-aged adults. Findings may contribute to targeted preventive strategies and novel therapeutic interventions, addressing the growing public health burden of age-related cognitive decline.

• Inclusion Criteria:

  • Adults aged 50 to 65 years (male and female)
  • Montreal Cognitive Assessment (MoCA) score ≥ 24
  • No participation in any structured exercise intervention in the last 6 months
  • No exposure to altitudes above 1,500 m in the preceding 3 months
  • No chronic kidney, cardiovascular, metabolic, neurological, or orthopedic -disease
  • No history of significant respiratory conditions (e.g., asthma, exercise-induced -bronchospasm, dyspnea on exertion)
  • No current immunosuppressive treatment (e.g., corticosteroids, antidepressants)
  • No history of cancer or arthritis treatments
  • No recent blood donation (within the last 2 months)
  • Must be covered by a Social Security system or equivalent
  • Signed informed consent after receiving clear and transparent study information
  • Eligibility confirmed by a medical doctor during the inclusion process

• Exclusion Criteria:

  • Active smoking
  • Major cardiovascular complications within the last 3 months (e.g., myocardial i-infarction, unstable angina, severe arrhythmias)
  • Severe hypertension (≥180 mmHg systolic or ≥110 mmHg diastolic)
  • Chronic respiratory insufficiency (e.g., COPD, sleep apnea)
  • Diabetes mellitus
  • Need for continuous or intermittent oxygen therapy
  • Participation in another clinical study at the same time
  • Use of corticosteroids or other systemic immunosuppressants
  • Any condition compromising safety or study compliance, as determined by the medical team
  • Pregnancy or breastfeeding
  • Legal or administrative protections (e.g., individuals under guardianship, persons deprived of liberty)
  • High baseline physical activity levels (PASE score >90 indicating moderate-to-intense physical activity)

males and females