Effects of Intermittent Hypoxia Protocols on Cognitive Performance and Brain Health in Older Adults Across Cognitive States: A Systematic Literature Review

Abstract

Background:

The rise in the aging population highlights the need to address cognitive decline and neurodegenerative diseases. Intermittent hypoxia (IH) protocols show promise in enhancing cognitive abilities and brain health.

Objective:

This review evaluates IH protocols’ benefits on cognition and brain health in older adults, regardless of cognitive status.

Methods:

A systematic search following PRISMA guidelines was conducted across four databases (PubMed, Scopus, Web of Science, and Cochrane Library) and two registers, covering records from inception to May 2024 (PROSPERO: CRD42023462177). Inclusion criteria were: 1) original research with quantitative details; 2) studies involving older adults, with or without cognitive impairment; 3) studies including IH protocols; 4) articles analyzing cognition and brain health in older adults.

Results:

Seven studies and five registered trials met the criteria. Findings indicate that Intermittent Hypoxia Training (IHT) and Intermittent Hypoxia-Hyperoxia Training (IHHT) improved cognitive functions and brain health. Intermittent Hypoxic Exposure (IHE) improved cerebral tissue oxygen saturation, middle cerebral arterial flow velocity, and cerebral vascular conductance, particularly in cognitively impaired populations. IHT and IHHT had no significant effect on BDNF levels. There is a lack of studies on IHHE in older adults with and without cognitive impairment.

Conclusions:

IH protocols may benefit cognition regardless of cognitive status. IHT and IHE positively affect cerebral outcomes, with all protocols having limited effects on BDNF levels. Future research should standardize IH protocols, investigate long-term cognitive effects, and explore neuroprotective biomarkers. Combining these protocols with physical exercise across diverse populations could refine interventions and guide targeted therapeutic strategies.

Keywords

Aging Alzheimer’s disease cognitive impairment cognitive performance intermittent hypoxia mild cognitive impairment older adults physical exercise

INTRODUCTION

The natural process of aging, in the absence of specific medical conditions (e.g., dementia), brings about a range of neurological and cognitive alterations, including shifts in memory retrieval, processing speed, and executive functions. 1 However, as life expectancy continues to increase, there is a concurrent rise in the prevalence of cognitive dysfunctions related to pathological conditions. Projections indicate that by 2030, the number of dementia cases is anticipated to reach 78 million and further escalate to 139 million by 2050, reflecting the growing concern for cognitive health in the aging population. 2 This trend has prompted researchers to explore various non-pharmacological therapies, such as cognitive stimulation, physical exercise training, reality orientation therapy, music therapy, reminiscence therapy, and others, as a means for curbing the progression of neurodegenerative diseases, alleviating their symptom manifestation, and preventing their onset. 3 Among these therapies, intermittent hypoxia (IH) has emerged as a promisingapproach.

While IH is a major component of obstructive sleep apnea syndrome, often leading to serious health issues including neurocognitive dysfunction, 4 a similarly based therapeutic approach with a lower hypoxic dose has emerged. As is often the case, the adage “dosis sola facit venenum” could be applied to the hypoxic conditioning method. This approach, known as Intermittent Hypoxia Exposure (IHE) when applied at rest or Intermittent Hypoxia Training (IHT) when combined with physical exercise, involves controlled, repeated cycles of oxygen-deficient gas mixtures interspersed with phases of normal oxygen levels (normoxia). Recognized as a non-invasive, non-pharmacological, and easy-to-implement technique, IHE holds considerable therapeutic promise.5,6, 5,6 In recent years, IHE and IHT have increasingly attracted the interest of the scholarly community, with an accumulating body of research investigating its effects in several contexts, including clinical and sports medicine, spanning a wide range of populations from healthy athletes to older adults. This includes older adults both with and without underlying health conditions. Multiple protocols of IH have been developed and implemented to quantify its impact.7,8, 7,8

When implementing IHE, the Fraction of Inspired Oxygen (% FiO₂) within the inhaled gas mixture is finely regulated, usually falling within the range of 10% to 15%. 9 A single session contains 4–8 cycles of variable duration ranging from 5 to 7 min for the hypoxic phase and 3 to 5 min for the reoxygenation phase. 9 Researchers have sought to enhance the therapeutic benefits of IHE, but they have encountered challenges. Increasing the number of IHE sessions tends to diminish its effectiveness, while reducing the oxygen levels below 10-11% is poorly tolerated by patients and can lead to adverse side effects. 9 As a response to these challenges, a novel approach has emerged in recent decades, intermittent hypoxia-hyperoxia exposure (IHHE), which involves combining hypoxic and hyperoxic periods (FiO₂ = 0.30–0.40) within the IHE regimen.9 –11 Additionally, this approach can also be combined with physical exercise, known as Intermittent Hypoxia-Hyperoxia Training (IHHT). This innovative combination therapy may extend the beneficial effects of IHE. 8

These methods may be of major interest in the fight against cognitive decline since they improve many of the physiological mechanisms currently responsible for early cognitive decline and the onset of neurodegenerative diseases such as high blood pressure, hyperglycemia, and inflammation.7,8, 7,8 IH protocols have shown diverse beneficial effects in older adults, spanning metabolic, cardiovascular, and pulmonary health. Specifically, IHT significantly improved the PaO₂/FiO₂ ratio post-thoracoscopic lobectomy in elderly patients with lung cancer, enhancing pulmonary function and reducing hospital stays. 12 Its efficacy extends to lowering blood pressure in young adults with stage 1 hypertension and boosting aerobic capacity in elderly males, with or without coronary artery disease.13,14, 13,14 Extended IHE exposure for 22 days enhanced blood lipid profiles in seniors with severe coronary artery disease. 15 Additionally, IHT reduced fasting glucose levels in prediabetes 16 and has been acknowledged in a systematic literature review as a promising method for improving overall health outcomes in healthy older adults. 7 Importantly, IHE and IHT also improved cognitive functions in both healthy and cognitively impaired older adults.17,18, 17,18 In another vein, IHHT highlighted its effectiveness in enhancing oxygen consumption, exercise tolerance, and cognitive function. 8 It notably reduced glucose levels and systolic and diastolic blood pressure, showing promise for treating coronary artery disease and improving cardiorespiratory fitness.19,20, 19,20 Research combining IHHE with multimodal training interventions (MTI) suggests improvements in physical, cognitive outcomes, and reduced pain in patients with mild cognitive impairment.21,22, 21,22

Furthermore, IHE and IHHE seem to elicit adaptive cellular responses that can potentially counteract aging and neurodegeneration. Initially, hypoxia stabilizes hypoxia-inducible factors (HIF-1α), which promote the transcription of genes that prepare the cell for low oxygen conditions. 23 Several biomarkers are triggered by HIF-1α as a result of hypoxic stimuli, including brain-derived neurotrophic factor (BDNF), which is involved in the growth, maintenance, and survival of neurons, erythropoietin, which enhances oxygen transport capacity by stimulating the production of red blood cells, improving oxygen delivery to tissues during hypoxic episodes, and vascular endothelial growth factor, which promotes angiogenesis, enhancing blood supply to tissues, facilitating improved oxygen and nutrient delivery as well as tissue repair and regeneration.23,24, 23,24 Subsequently, during reoxygenation, an increased production of reactive oxygen species activates the nuclear factor erythroid 2-related factor 2 (Nrf2).25,26, 25,26 This dual action of HIF-1α and Nrf2, along with other intermediate molecules, stimulates genes for antioxidation, anti-inflammatory responses, cellular defense, and repair mechanisms,27,28, 27,28 in line with the inflamm-aging paradigm 29 and the free radical theory of aging. 30 These theories posit that neuroinflammation, oxidative stress, and the resultant damage to vital macromolecules are primary drivers of the aging process.31,32, 31,32 By enhancing cellular defenses and reducing oxidative stress, IH protocols show promise in mitigating these age-related changes, thus potentially slowing or altering the course of neurodegeneration. 33

Moreover, as shown by animal models,34 –36 physical exercise, by improving mitochondrial function, reducing oxidative stress, modulating apoptotic and autophagic pathways, and promoting neurogenesis can provide a multi-faceted approach to neuroprotection in several neurodegenerative diseases, including Alzheimer’s disease. These improvements at the cellular level can help maintain neuronal health, potentially slowing down or mitigating the progression of Alzheimer’s disease. As such, regular physical exercise may therefore be considered a non-pharmacological intervention to support brain health, promote cognitive resilience, and combat neurodegenerative diseases like Alzheimer’s disease, especially if combined with IH.

To date, the existing body of scientific research has not yet been thoroughly examined through a systematic review focusing specifically on the effects of IH protocols on cognitive function and brain-related outcomes in older adults, regardless of their cognitive impairment status. Recognizing this gap in knowledge, our systematic review aims to provide a detailed synthesis and critical evaluation of the research on the influence of IH protocols in improving cognitive performance among the elderly, highlighting the potential of these interventions as innovative solutions to combat the challenges posed by aging and neurodegeneration.

METHODS

This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines “PRISMA 2020”. 37 It was officially registered on the International Database of Systematic Review Protocols, PROSPERO, under the registration number: PROSPERO 2023: CRD42023462177.

Search strategy

We conducted a comprehensive search across four prominent scholarly databases, namely MEDLINE, accessed through the freely available PubMed interface, Scopus, Cochrane Library, and Web of Science, without imposing any time or language restrictions. The literature search spanned from the earliest available records up to 15 May 2024. The search string consisted of three major components: “Intermittent hypoxia” and its relationship to “Cognitive performance” in both “healthy” and “cognitively impaired” old adults, with synonyms/variants properly linked by using Boolean operators “AND, OR”. We employed the following search terms across all the above-mentioned: [(intermittent hypoxia) OR (intermittent hypoxic training) OR (intermittent hypoxia training) OR (intermittent hypoxia exposure) OR (interval hypoxic training) OR (intermittent hypoxia-hyperoxia) OR (chronic intermittent hypoxia) OR (exposure to intermittent hypoxia) OR (intermittent hypoxia-normoxia)] AND [(cognition) OR (cognitive function) OR (cognitive performance) OR (cognitive dysfunction) OR (cognitive disorders) OR (brain) OR (brain health) OR (cerebral)] AND [(Alzheimer) OR (Alzheimer’s disease) OR (mild cognitive impairment) OR (cognitively impaired) OR (dementia) OR (geriatric) OR (old) OR (elderly) OR (adults) OR (healthy adults) OR (aged) or(aging)].

Controlled vocabulary, including medical subject headings (MeSH), as well as wild-card options (i.e., truncated words, dollar sign), were used when appropriate. Moreover, grey literature was thoroughly searched for additional studies via the GreyNet portal. Additionally, registers were searched through ClinicalTrials.gov and the WHO International Clinical Trials Registry platform. The reference lists of the selected articles were manually reviewed to identify any additional articles that could potentially meet the inclusion criteria. Details on the search strategy used are provided in Supplementary Table 1.

Eligibility criteria

Inclusion and exclusion criteria were devised according to the PICOS/PECOS mnemonic: P (population), old adults with or without cognitive impairments, I/E (intervention/exposure), exposed to any IHT Protocol or undergoing interventional programs including any IH Protocol, C (comparison/comparator), (cognitively impaired versus non-cognitively impaired old adults, exposed to any IH protocol versus not exposed), O (outcome), Cognitive performance, and S (study design), original research with sufficient quantitative details. Animal studies, as well as research investigating the effect of IH on obstructive sleep apnea syndrome, were excluded from consideration in the current systematic review. Additionally, we excluded letters to the editor, editorials, commentaries, technical notes, clinical cases, and reports. Reviews, if existing, were scanned to ensure relevant literature coverage but were not retained in the present study. Our inclusion and exclusion criteria were established after an initial familiarization with the literature and with guidance from a librarian and an expert in research methodology, evidence-based medicine, and systematic reviews.

Study selection

Following the removal of duplicate entries using the EndNote software, the search results underwent an independent screening process conducted by two researchers, namely AB and CF, following the predefined eligibility criteria using COVIDENCE (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia, http://www.covidence.org). Any discrepancies in their assessments were resolved through either deliberation or by involving a third researcher, OD. Articles that could not be definitively excluded based on title or abstract underwent a comprehensive examination, referred to as a full-text review, to determine their suitability for inclusion.

Data extraction

The lead investigator extracted data, organizing the information into descriptive tables. Subsequently, another investigator cross-checked the data for accuracy and consistency. The following data were extracted: first author of the study, year of publication, study country, study design, sample size employed, a priori sample size calculation, participants’ characteristics (health status, sex, age, ethnicity, body height, body mass, and body mass index or BMI, smoking status, alcohol intake, comorbidities, use of drugs), study duration, intervention/exposure duration and frequency, follow-up period, IH regime, number of total sessions across the intervention duration, number of sessions per week, duration of each session, intra-session frequency (number of cycles), duration of a single hypoxic/hyperoxic or hypoxic/normoxic period, % FiO₂ or SpO₂, % SaO₂, ScO₂, inter-session frequency, hypoxic test executed before intervention, other interventions combined if available, cognitive measures, brain health measures, and outcomes. A specifically designed Excel spreadsheet was used for the purpose. The data presented in the figures was extracted using PlotDigitizer software. Additional details regarding the extracted data can be found in Supplementary Tables 2–6.

Risk of bias and methodological quality assessment

The risk of bias was assessed using a modified version of the Downs and Black checklist, 38 which evaluates the methodological quality of both randomized controlled and non-randomized studies. The Downs and Black checklist has been demonstrated to exhibit good intra-rater (r = 0.88) and inter-rater (r = 0.75) reliability. 38 This checklist comprises four evaluation domains: reporting (items 1–10), external validity (items 11–13), internal validity (items 14–26), and statistical power (item 27).

We made minor adjustments to the checklist, particularly to item 27 which pertains to statistical power. We used the same scoring system as for the other items, transitioning from the original ‘0–5’ scale to ‘no = 0, unable to determine = 0, and yes = 1’.39,40, 39,40 All items were rated on a scale where one point was given for meeting the criterion, and zero points were given for not meeting the criterion or when it could not be determined. The only exception was item 5 which received two points if the essential confounders (Age, Sex, BMI, Training status, and Health status) were provided, one point if confounders were partially furnished, and zero points if the criterion was not met or remained unclear. A detailed summary of the items used and their respective scores can be found in Supplementary Table 7. The overall scores ranged from 0 to 28 points with higher scores reflecting higher-quality research. Studies were classified based on their sum scores into distinct quality categories as follows: good quality (score: 20–28 points), moderate quality (score: 11–19 points), and low quality (score: <11 points).8,39, 8,39 In the case of disagreements, the two reviewers (AB and NLB) engaged in discussions to reach a resolution, and if consensus remained elusive, a third reviewer (OD) was brought in forconsultation.

RESULTS

Search results

The preliminary literature search revealed 608 items (603 from databases and 5 from registers). No additional studies were identified through gray literature. Initially, 202 items were identified as duplicates and subsequently removed. Following this, 406 articles underwent screening based on their titles and/or abstracts, resulting in the exclusion of 388 of them. Eighteen articles were subjected to in-depth assessment. After a thorough examination of their full texts, two studies were excluded due to the unavailability of English versions (papers written in Russian), preventing comprehensive analysis. Additionally, two other papers were excluded for focusing on the wrong population. One paper was excluded because it was retracted during the manuscript writing. Another paper was excluded based on serious concerns raised on PubPeer, indicating potential issues such as data manipulation. Ensuring the reliability of our sources is crucial, and AI-enhanced quality checks, including consultations of websites like PubPeer, and Retraction Watch help maintain the credibility of our review.41,42, 41,42 Seven studies were ultimately retained for inclusion in this systematic review.17,18,21,43–46 , 17,18,21,43–46 The flow diagram adopted in the present study is pictorially shown in Fig. 1. In this systematic review, a meta-analysis was not feasible due to substantial heterogeneity among the included studies.

Fig. 1

PRISMA flow diagram adopted in the present study.

Risk of bias and methodological quality

Following the application of the modified Downs and Black checklist for assessing bias and methodological quality, our examination revealed that the included studies achieved an average score of 20.7, with a median of 20 points (range: from 18 to 23). Out of the seven studies, five were classified as high-quality (>19 points),17,21,43–45 , 17,21,43–45 and the rest of the studies were rated as being of moderate quality (18 points). A consistent limitation across all included studies pertaining to issues related to their internal validity and the absence of power analysis. In all included studies, full scores were obtained on 13 items (namely, items 1, 2, 3, 6, 7, 8, 11, 12, 13, 16, 17, 18, and 20). However, it is noteworthy that item 24 (“Was the randomized intervention assignment concealed from both participants and health care staff until recruitment was complete and irrevocable?”), item 15 (“Was an attempt made to blind those measuring the main outcomes of the intervention?”), and item 19 (“Was compliance with the intervention/s reliable?) received a uniform rating of 0 in all studies. Table 1 displays the summary of the risk of bias and the methodological quality assessment.

Table 1

Results of Risk of Bias assessment evaluated using the modified Downs and Black Check List

Domains	Items	Bayer et al. 21	Wang et al. 18	Schega et al. 44	Behrendt et al. 47	Schega et al. 17	Liu et al. 46	Behrendt et al. 45
Reported	1	1	1	1	1	1	1	1
	2	1	1	1	1	1	1	1
	3	1	1	1	1	1	1	1
	4	1	1	1	1	1	0	1
	5	1	1	1	2	2	1	2
	6	1	1	1	1	1	1	1
	7	1	1	1	1	1	1	1
	8	1	1	1	1	1	1	1
	9	1	0	0	0	0	0	0
	10	1	1	1	1	1	1	1
External validity	11	1	1	1	1	1	0	1
	12	1	1	1	1	1	0	1
	13	1	1	1	1	1	1	1
Internal Validity	14	1	0	1	1	1	1	1
	15	0	0	0	0	0	0	0
	16	1	1	1	1	1	1	1
	17	1	1	1	1	1	1	1
	18	1	1	1	1	1	1	1
	19	0	0	0	0	0	0	0
	20	1	1	1	1	1	1	1
	21	1	1	1	1	1	1	1
	22	0	0	0	0	0	0	0
	23	1	0	1	1	0	1	1
	24	0	0	0	0	0	0	0
	25	1	1	1	1	0	0	1
	26	1	0	1	1	1	1	1
Power	27	0	0	0	1	0	0	1
	Total score	22	18	21	23	20	18	23

Participants and study characteristics

The year of publication ranges from 2013 to 2024. The included studies in our systematic review were primarily conducted in countries of the Global North. Specifically, four studies were from Germany, two from the United States, and one from Australia. In terms of study design, the included studies were classified as follows: four were Randomized Controlled Trials,21,44,45,47 , 21,44,45,47 two were pilot studies,17,18, 17,18 and one was a case-controlled repeated-measure study. 46 Across these studies, a total of 182 participants were involved, of which 92 were healthy and 90 had cognitive impairment. All included studies employed mixed-gender samples, with a consistent pattern of higher female representation across all of them. The outcomes were not disaggregated by sex or gender. Among the seven studies included in our review, three acknowledged this limitation and attributed it to small sample sizes.21,46,47 , 21,46,47 The remaining four studies did not address or justify the absence of sex or gender disaggregation in their data. In addition, four studies focused on the impact of IH protocols on elderly individuals with cognitive impairment, including mild cognitive impairment, Alzheimer’s disease, vascular dementia, and other dementias.18,21,45,47 , 18,21,45,47 Three studies assessed the effects on elderly individuals without cognitive impairment.17,44,46 , 17,44,46 However, no studies compared the effects on both cognitively impaired and non-cognitively impaired elderly populations. Main information, including sample size, age, sex, and health status, is reported in Table 2, while more detailed characteristics are provided in Supplementary Tables 2–6.

Table 2

Characteristics of included studies

References	Design	Participants characteristics			Experimental groups	Intervention characteristics
		Sample size and sex	Age	with/without CIM		Duration/Frequency	FiO₂ or SpO₂
Liu et al. 46	Comparative study	n = 25 (12 elderly: 7 females, 13 young: 5 females)	Elderly: 71±2 y, Young: 24±1 y	Non-CIM	IHE both groups	▪ Weeks: NR ▪ 5 sessions ▪ Training density: NR ▪ 5 cycles/ session ▪ 50 min/session	▪ Hypoxia FiO₂ = 10 0.2% ▪ Normoxia: NR
Behrendt et al. 43	RCT	n = 25(1 male, 24 females)	77–94 y	AD, Vascular dementia, and Unspecified dementia	▪ PA+IHHE (n = 14) ▪ PA+Sham IHHE (n = 11)	▪ 6 weeks▪ 3 sessions/week (18 sessions) ▪ Training density: NR▪ Number of cycles: NR▪ 30 min/session	▪ Hypoxia FiO₂ = 10% –14% ▪ Hyperoxia FiO₂ = 30% –40%
Schega et al. 17	Pilot study	n = 34 (8 males; 16 females	60–70 y	Non-CIM	▪ IHT+PA (n = 17) ▪ Sham IHT+PA (n = 17)	▪ 6 weeks ▪ 3 sessions/week (18 sessions) ▪ Training density: NR▪ Number of cycles: NR▪ 60 min/session	▪ Hypoxia based on SpO₂ = 80% ▪ Normoxia: NR
Behrendt et al. 45	RCT	n = 24 (2 males/ 22 females)	83.1±5.0 y	AD, Vascular dementia, Mixed types of dementia	IHHE + PA (n = 12) PA+Sham IHHE (n = 12)	▪ 6 weeks▪ 3 sessions/week (17 sessions) ▪ Training density: NR▪ IG: 4–8 cycles▪ IG: NR / CG = 20 min	▪ Hypoxia = 10–14% ▪ Hyperoxia = 30–40%
Bayer et al. 21	RCT	n = 34 (7 males, 27 females	64–92 y	MCI	▪ IHHE+PA (n = 18)▪ Sham IHHE+PA (n = 16)	▪ 5–7 weeks▪ 2-3 sessions/week (16–20 sessions) ▪ Training density: NR▪ 4–8 cycles/session▪ 30–40 min/session	▪ Hypoxia FiO2 = 12% ▪ Hyperoxia FiO2 = 35%
Wang et al. 18	Pilot study	n = 7 (1 male, 6 females)	58–78 y	MCI	IHE (n = 7)	▪ 8 weeks▪ 3 sessions/week (24 sessions) ▪ Training density: NR▪ 8 cycles/session▪ 40 min/session	▪ Hypoxia FiO2 = 10% + 0.1▪ Normoxia: NR
Schega et al. 44	RCT	n = 33 (19 males/17 females)	60–75 y	No.CIM	▪ IHT(n = 18) +PA▪ Sham IHT +PA (n = 18)	▪ 4 weeks▪ 3 sessions/ week (12 sessions) ▪ Training density: NR▪ Number of cycles: NR▪ 90 min/session	▪ Hypoxia based on SpO₂ = 80% ▪ Normoxia: NR

↑ indicates significant increase in the study variable; ↓ indicates significant decrease in the study variable; ↔ indicates that the study variable remains unchanged; IG, intervention; CG, control group; RCT, randomized controlled trial; AD, Alzheimer’s disease; Non-CIM, non-cognitively impaired; MCI, mild cognitive impairment; FiO2, fraction of inspired; IHT, intermittent hypoxia training; IHHT, intermittent hypoxia-hyperoxia training; IHE, intermittent hypoxia exposure; IHHE, intermittent hypoxia-hyperoxia exposure; CDT, Clock Drawing Test; CVLT-II, verbal learning test-second edition; TMT-B, trail making test-B; COWAT, controlled oral word association test; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; DemTect, Dementia-Detection Test; ZVT, Zahlen-Verbindungs-Test; ScO₂, cerebral tissue O2 saturation; V_MCA, middle cerebral arterial flow velocity; CVC, estimated cerebral vascular conductance; BDNF, brain-derived neurotrophic factor; NA, not Available; NR, not reported.

Different intermittent hypoxia protocols characteristics

The duration of the intervention is highly variable, from 3 to 8 weeks and with the frequency of sessions from 2 to 5 per week. The duration of each session varied from 30 to 90 min per session. The total number of sessions across the intervention period was also widely variable ranging from 5 sessions to 24. Among the included studies, three primarily utilized the IHHT protocol.21,45,47 , 21,45,47 while the remaining studies utilized IHE and IHT.17,18,44,46 , 17,18,44,46 Notably, no studies used the IHHE protocol. Furthermore, five studies combined IH protocol with physical exercise.17,21,44,45,47 , 17,21,44,45,47 The physical exercise regimens included MTI (comprising cardiovascular fitness training combined with strength training), 21 aerobic training,44,45,47 , 44,45,47 and strength endurance training. 17

In the IHE and IHT protocol, the intensity of the hypoxia phase ranged from FiO₂ = 10.0% to 11.0% or SpO₂ = 85% –90%. On the other hand, for IHHT, the hypoxia and hyperoxia phases ranged from FiO₂ = 10.0% to 14.0% and FiO₂ = 30.0% to 40.0%, respectively. Only four studies reported the number of cycles per session, with variations ranging from 4 to 8 cycles.18,21,48,49 , 18,21,48,49 The inter-session frequency was not reported in any of the included studies. Furthermore, only three studies, conducted by Bayer et al. 21 and Behrendt et al.45,47, 45,47 incorporated an hypoxic test before the intervention. All studies used normobaric hypoxia administered via a face mask.17,18,21,44–47 , 17,18,21,44–47 One study included a follow-up assessment three weeks after the conclusion of the intervention. 44 The main characteristics of the IH protocols used in the included studies are summarized in Table 2.

Effects of different intermittent hypoxia protocols on cognitive performance and brain health

The included studies examined the effects of various IH protocols, specifically IHE/IHT and IHHT, on multiple cognitive performance domains, such as executive functions, attention, and verbal memory, as well as cerebral hemodynamics among older adults with18,21,45,47 , 18,21,45,47 or without cognitive impairment.17,44,46 , 17,44,46 Additionally, some studies explored the impact of these interventions on brain-related outcomes, including cerebral tissue oxygen saturation (ScO₂), neutrophil extracellular traps, middle cerebral arterial flow velocity (V_MCA), estimated cerebral vascular conductance (CVC), and BDNF.18,45,46 , 18,45,46 Furthermore, one study assessed inflammatory biomarkers, including interleukin-6 (IL-6) and C-reactive protein (CRP). Tables 3 and 4 provide an overview of the cognitive domains assessed in the reviewed studies, detailing the specific tests used for each domain and the number of studies that explored these areas.

Table 3

Summary of measurements and outcomes of the included studies

References	Intervention	Measurements	Cognitive Outcomes	Other Brain-health Outcomes
Liu et al. 46	HE	V_MCA, CVC, ScO₂	NA	▪ VMCA: ↑ (greater in young) (Age: p = 0.012, Bout: p = 0.001),▪ ScO₂: ↓ (smaller in elderly) (Age: p < 0.001, Bout: p = 0.001),▪ CVC: ↑ (smaller in elderly) (Age: p < 0.001, Bout: p = 0.001)
Behrendt et al. 43	IHHT	DemTect /CDT	▪ ↑DemTect (p = 0.007)▪ ↔CDT (p = 0.277)	NA
Schega et al. 17	IHT	MMSE/d2/ZVT	▪ ↔MMSE (p = NA)▪ ↑d2 (p = 0.000)▪ ↑ZVT(p = 0.000)	NA
Bayer et al. 21	IHT	DemTect /CDT	▪ ↑ DemTect (p < 0.001)▪ ↑ CDT (p = 0.031)	NA
Wang et al. 18	IHE	MMSE/ CVLT-II/TMT-B, COWAT/Digit span/ScO₂/VMCA/CVC	▪ ↑MMSE(p = 0.038)▪ ↔ CVLT-II (p = 0.102) ▪ ↔ TMT-B (p = 0.280) ▪ ↔ COWAT (p = 0.285)▪ ↑ Digit span (p = 0.047)	▪ ↑ ScO_2 (p = 0.004)▪ ↑V_MCA (p = 0.044)▪ ↑CVC (p = 0.003)
Schega et al. 44	IHT	Stroop Test/BDNF	▪ ↑Word-Color-Task: pre-post: IG (p = 0.005)/ CG (p = 0.005)▪ Pre-follow up: IG (p = 0.000), CG (p = 0.028)▪ ↑Color-Task: Pre-follow up: IG (p = 0.004)▪ ↔Word-Task (p = NA)	▪ ↔BDNF-Levels: pre-post (p = 0.766), pre-follow-up (p = 0.573) for both groups
Behrendt et al. 45	IHHT	BDNF_S/BDNF_P/BDNF_S/_P-ratio/IL-6/CRP/ MMSE	MMSE was assessed only pre-intervention	▪ Acute effects:BDNFS: ↔ IG and CG (p = 1.000) BDNFP: ↔ IG and CG (p = 1.000) BDNFS/P-ratio: ↔ IG and CG (p = 1.000) IL-6: ↔ IG and CG (p = 1.000) CRP: ↔ IG and CG (p = 1.000)▪ Chronic effects:BDNFS: ↔ IG and CG BDNFP: ↔ IG (p = 0.139) and CG (p = 0.478) BDNFS/P-ratio: ↔ IG (p = 1.000) and CG (p = 0.243) CRP: ↔ IG and CG IL-6: ↔ IG(p = 1.000) and CG (p = 0.243)

BDNF_S, brain-derived neurotrophic factor serum blood concentration; BDNF_P. brain-derived neurotrophic factor plasma blood concentration; IL-6, interleukin-6; CRP, C-reactive protein; CDT: Clock Drawing Test; CVLT-II, verbal learning test-second edition; TMT-B, trail making test-B; COWAT, controlled oral word association test; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; DemTect, Dementia-Detection Test; ZVT, Zahlen-Verbindungs-Test; ScO₂, cerebral tissue O2 saturation; V_MCA, middle cerebral arterial flow velocity; CVC, estimated cerebral vascular conductance; NA, not available.

Table 4

Summary of cognitive domains, associated tests, and research incidence

Cognitive functions domains	Cognitive tests	Number of studies
Overall cognitive functions	MMSE	217,18, 17,18
	DemTect	221,47, 21,47
Attention	CDT	221,47, 21,47
	d2 test	1 17
Executive function	Stroop (Word-task/ Color-task/Word-Color-Task)	1 44
	CDT	221,47, 21,47
	TMT-B	1 18
Information-processing speed	ZVT	1 17
Verbal fluency	COWAT	1 18
Visuospatial abilities	CDT	221,47, 21,47
Motor programming	CDT	221,47, 21,47
Memory	Digit Span	1 18
	CVLT-II	1 18

MMSE, Mini-Mental State Examination; CDT, Clock Drawing Test; TMT-B, Trail Making Test-B; ZVT, Number Combination Test; COWAT, Controlled Oral Word Association Test; CVLT-II, California Verbal LearningTest II.

Effects on non-cognitively impaired old adults

Three studies were conducted to investigate the impact of IH protocols on the cognitive functions and brain health of elderly individuals without cognitive impairments, with study durations ranging from 4 to 6 weeks. These studies evaluated a range of outcomes using various measurement tools or tests. Cognitive performance was assessed through a battery of tests, including the Stroop test (Word-Task, Color-Task, and Word-Color-Task), the Mini-Mental State Examination (MMSE), the d2 test, and the Number Combination Test (ZVT). Additionally, brain-related outcomes were measured using the ScO₂, V_MCA, and CVC.17,44,46 , 17,44,46 All of these three studies implemented a hypoxia-normoxia protocol. Two of them integrated IHE with physical exercises encompassing aerobic, strength, and endurance training,17,44, 17,44 while only one study used IHE solely. 46 The aerobic exercise was administered at an intensity ranging between 65% to 75% of their maximum heart rate, 44 while the strength and endurance exercises were set at 50% of their maximum force. 17

The first study, conducted by Schega et al. 44 demonstrated that after four weeks of IHE combined with 30 min of aerobic training three times a week, improvements were observed in the Word-Color-Task performance for both the IHE+PA and Sham IHE+PA groups in both the pre-post and pre-follow-up assessments. Additionally, the Color-Task performance improved in the pre-follow-up assessment for the IHE+PA group. However, the Word-Task performance remained unchanged for both groups. Furthermore, this program did not have any significant impact on the levels of BDNF for either group. 44

The second study included in this analysis revealed that a six-week combined regimen of IHE along with strength and endurance training, conducted at 50% of participants’ maximum capacity three times per week, resulted in improvements in the domains of attention, as measured by the d2 test, and information-processing speed, as indicated by the results on the ZVT test. Notably, the MMSE scores remained unchanged for both groups. 17

The third study conducted by Liu et al. 46 investigated the effects of IHE on cerebrovascular and cardio-ventilatory responses in elderly and young adults. The study showed that the elderly group exhibited a significant decrease in ScO₂ during hypoxia, though the reduction was less pronounced compared to the young group. Similarly, the V_MCA and CVC increased during hypoxia in both groups, with the young group showing more substantial increases.

While one study demonstrated improvements in cognitive inhibition, as measured by the Stroop Word-Color-Task performance, 44 another study indicated benefits in attention, as assessed by the d2 test, and information-processing speed using the ZVT test. 17 This suggests that the impact of IHT protocols may differ across various cognitive tasks. The findings from both studies suggest that specific cognitive functions, such as attention and information-processing speed, can be enhanced when IHT training is combined with physical activity. However, it is important to note that the IHT protocols did not produce a significant overall impact on cognitive function. Table 3 summarizes the main measurements andoutcomes.

Effects on cognitively impaired old adults

Regarding cognitively impaired older adults, four studies were included,18,21,45,47 , 18,21,45,47 each investigating IH protocols in this population, with a duration spanning from 3 to 8 weeks. The studies assessed various outcomes, including Montreal Cognitive Assessment (MoCA), DemTect, MMSE, Clock Drawing Test (CDT), and Digit Span test, as well as other parameters like biomarkers associated with Alzheimer’s disease like serum (BDNF_S) and plasma (BDNF_P) BDNF levels, ScO₂, CVC, and V_MCA.

Regardless of the specific outcome measures, improvements were consistently observed in overall cognitive functions and cerebral hemodynamics following the administration of either IHT or IHHT, whether applied individually or in combination with physical exercise.

In the context of combining IHHE with other interventions, Behrendt et al. 47 demonstrated that a 6-week IHHE program, followed by aerobic cycling training conducted three times per week (IHHT), led to an improvement in cognitive functions as measured by the DemTect and CDT tests. This study included patients with various types of dementia, such as Alzheimer’s disease, vascular dementia, and unspecified dementia. Bayer et al. 21 further explored the synergistic effects of combining IHHE with other interventions. Their study revealed that an IHHE program, when integrated with a MTI involving cardiovascular fitness and strength training, administered 2-3 times per week over 5-6 weeks, resulted in an enhancement of overall cognitive functions. This improvement was assessed by comparing the DemTect and CDT scores in the MTI+IHHE group to those in the group that underwent the same multimodal program combined sequentially on the same day with sham IHHT.

A second study conducted by Behrendt et al. 45 , which used the same protocol as their earlier study reported in our systematic review, showed that the addition of 30 min of IHHE prior to 20 min of aerobic cycling did not significantly increase BDNF_S and BDNF_P levels or reduce IL-6 and CRP levels in geriatric patients after a 6-week intervention. The study highlighted that there were no significant within-group differences from pre- to post-exercise for these biomarkers, indicating that this combined intervention may not be effective for modulating these specific inflammatory and neurotrophic markers in older adults with various types of dementia.

Lastly, a pilot study unveiled that eight weeks of IHE, conducted in three sessions per week, resulted in enhancements in overall cognitive performance and short-term memory as measured by the MMSE and Digit Span tests, respectively. However, there was no observed improvement in verbal memory and learning, executive functions, or verbal fluency when assessed using the California Verbal Learning Test II (CVLT-II), Trail Making Test-B (TMT-B), and Controlled Oral Word Association Test (COWAT), respectively. Moreover, an increase of ScO₂, CVC, and V_MCA was observed, indicating that IHT by itself may improve cerebral blood flow and oxygenation. 18

In summary, there is a consistent observation across multiple studies that IHHT can lead to improvements in cognitive performance. Bayer et al. 21 and Behrendt et al. 47 noted enhancements in DemTect and CDT scores. These improvements were typically not observed in control groups receiving sham IHHT. Studies by Bayer et al. 21 and Behrendt et al. 47 suggest that combining IHHT with physical training, such as cardiovascular and strength exercises, can amplify cognitive benefits. Furthermore, IHE can have a significant effect on cognitive performance and cerebral hemodynamics. The main measurements and outcomes are summarized in Table 3.

DISCUSSION

This systematic review comprehensively analyzed seven studies that investigated the impact of IHT/IHE and IHHT on cognitive performance and brain-related outcomes in older individuals, both with and without cognitive impairments.17,18,21,44,46–48 , 17,18,21,44,46–48 The included studies implemented IHT/IHE or IHHT either as standalone interventions or in combination with physical exercise. The intervention durations range from 3 to 8 weeks. Among these studies, four specifically examined the effects on cognitively impaired older adults,18,21,45,47 , 18,21,45,47 with three employing IHHT 21,45,47 , 21,45,47 and one using IHT. 18 In contrast, for non-cognitively impaired older adults,17,44,46 , 17,44,46 only three studies investigated the effects of IHT in combination with various types of physical exercise, including aerobic, 44 strength, and endurance training. 17 Moreover, one study used IHE as a standalone intervention. 46

Effects of different hypoxia training protocols on cognitive performance

Non-cognitively impaired old adults

This systematic review identified a limited number of studies examining the impact of IHT on cognitive functions in non-cognitively impaired older adults. Only two studies investigated this intervention in this population.17,44, 17,44 It is important to note that out of these two studies, only one examined the effect of IHT on overall cognitive performance as measured by MMSE. 17 The results of this study indicated that the MMSE scores remained unchanged after the implementation of the IHT program in combination with a physical activity program.

The fact that there is only one study available for analysis highlights a significant limitation in the current body of research, and as such, it would be premature to generalize the results or draw definitive conclusions based on this limited evidence. To enhance our understanding of the potential cognitive benefits of IHT in non-cognitively impaired older adults, further studies are needed to expand and deepen this area of research.

The lack of observed effects may also be attributed to the potential limitations of the assessment tool in detecting improvements in the specific cognitive state and stage investigated. The MMSE is a widely used screening tool but may not be sensitive enough to capture subtle changes in cognitive function, particularly in populations with minimal cognitive impairment. Given these limitations, it is imperative to investigate the efficacy of alternative, more sensitive cognitive assessment tools, such as MoCA which could provide a more accurate evaluation of cognitive changes.50,51, 50,51 Additionally, the same study conducted by Schega et al. 17 not only showed no improvements in the MMSE scores but also highlighted some noteworthy findings. Specifically, their research demonstrated an enhancement in attention, as measured by the d2 test, and improvements in information-processing speed, assessed using the ZVT test. These results raise the intriguing possibility that while MMSE may not capture changes, other cognitive domains and functions, such as executive functions, memory, and language, could potentially benefit from the combined intervention of IHT and physical activity.

The findings by Liu et al. 46 showed that the elderly group exhibited a significant decrease in the ScO₂ during hypoxia, though the reduction was less pronounced compared to the young group. This indicates that elderly individuals have a relatively preserved cerebral oxygenation response, which might be attributed to lower metabolic demands and reduced cerebral perfusion associated with aging. 52 Additionally, the study reported increases in the V_MCA and CVC during hypoxia in both age groups. However, the increases were more substantial in the young group, highlighting an age-related attenuation in cerebrovascular responsiveness. The elderly participants demonstrated less robust increases in V_MCA and CVC, suggesting diminished cerebrovascular reserves and possibly impaired neurovascular coupling or endothelial function. Despite these differences in V_MCA and CVC between young and older adults, the study highlights that IHE remains beneficial for the elderly.

In another vein, previous studies have shown that IHHT, as a variation of IHT, may offer a more effective approach in enhancing several functions, including cognitive performance, in older adults with cognitive impairments.19,21,22 , 19,21,22 This suggests an intriguing avenue for further exploration assessing the impact of IHHT in older adults without cognitive impairments. Implementing IHHT in such a population may reveal a significant improvement in overall cognitive performance, potentially addressing the absence of effects observed when IHT was utilized. 17

Cognitively impaired old adults

Of the seven included studies, four assessed the effects of different IH protocols in cognitively impaired older adults.18,21,47,48 , 18,21,47,48 Among these, three studies utilized IHHT.21,47,48 , 21,47,48 Out of these three studies, two combined IHHT with a physical exercise program,21,47, 21,47 while one study specifically employed IHT. 18 Three studies evaluated the effects on patients with mild cognitive impairment, with one study having a broader focus, including populations with Alzheimer’s disease, vascular dementia, and unspecified dementia.

Across all included studies, a significant improvement in overall cognitive performance was consistently observed as measured by widely recognized assessments such as MMSE, DemTect, and MoCA. This finding underscores that, regardless of the cognitive impairment level, the disease or the intervention modality used, both IHT and IHHT may be effective in enhancing cognitive performance in this older population. However, given the limited number of available studies, additional research is necessary to gain a deeper understanding of these effects. Further investigations are needed to explore the combined effects of IHE and physical exercise programs on various populations, including those with different types of neurodegenerative diseases.

Prior research, encompassing studies on both humans and animals, has firmly identified the shared mechanisms of neurodegeneration, aging, and hypoxia conditioning, including processes such as neuroinflammation, oxidative stress, and mitochondrial dysfunction.33,53, 33,53 These commonalities suggest that targeting these factors through intermittent hypoxic conditioning, with the appropriate dosage and modality, may offer an effective intervention to prevent neuronal degeneration. 33 Furthermore, such interventions may also stimulate neurogenesis 54 and neuro-regeneration, 55 potentially serving as treatments for neurodegenerative diseases, such as Alzheimer’s disease56,57, 56,57 and Huntington’sdisease. 58

The study conducted by Bayer and colleagues 21 revealed that enhanced global cognitive performance was observed solely in individuals with mild cognitive impairment who engaged in both the MTI and IHHT. They reasoned that the absence of cognitive improvements in patients who underwent the multimodal training program alongside a placebo IHHT could be attributed to their limited initial fitness levels, which prevented them from engaging in training with an exercise intensity high enough to induce measurable cognitive enhancements. Consequently, the enhancements in cognitive performance may be associated with the influence of IHHT. These findings align with the results reported by Behrendt et al. 47 However, it is worth noting that Bayer et al. 21 identified positive impacts on cognitive functions, particularly those measured using CDT, which were not observed in Behrendt et al.’s study. 47 The absence of improvement in the CDT may be linked to the particular type of physical exercise program used, emphasizing that a multimodal training regimen, when combined with IHHE, could potentially be more efficient than aerobic exercise when combined with IHHE. Additional research is required to solidify and corroborate these findings.

Despite previous animal and human studies suggesting that hypoxia can increase BDNF protein transcription and reduce systemic inflammatory cytokine responses, the study of Behrendt et al. 45 found that IHHT had no significant effect on these biomarkers. The authors attributed the lack of improvement in BDNF and inflammatory biomarkers to several key factors. Firstly, the aerobic exercise sessions were of low intensity and short duration, likely insufficient to significantly increase BDNF levels, which typically respond better to higher intensity and longer duration exercise.59 –61 Additionally, the characteristics of the hypoxic stimulus, including its intensity, duration, frequency, and method, might not have been optimal to induce significant changes in BDNF expression and anti-inflammatory responses. 56 The small sample size and large variability in basal BDNF levels may have contributed to the lack of significant findings.59,62, 59,62 Furthermore, the study population consisted of geriatric patients with multiple chronic diseases and cognitive impairments, potentially influencing the results and limiting generalizability. Finally, the hypoxic dose might have been too low to elicit significant anti-inflammatory effects, as moderate to low doses are generally needed to activate beneficial redox signalingpathways. 63

The potential mechanisms behind the cognitive improvements observed with IH, combined or not with exercise, in adults with neurodegenerative diseases can be attributed to several cellular responses that promote neuroprotection and neuroplasticity. Intermittent hypoxia has been shown to induce a HIF-1α response, which regulates the expression of various genes involved in neuroprotection, angiogenesis, and metabolic adaptation. This includes the upregulation of vascular endothelial growth factor, erythropoietin, and BDNF.23,33, 23,33 BDNF, in particular, plays a crucial role in promoting neuroplasticity, synaptic plasticity, and survival of neurons, which are essential for maintaining cognitive function and countering age-related cognitive decline. 64 Furthermore, hypoxia conditioning has been associated with enhanced mitochondrial biogenesis and function, reduction in oxidative stress, and modulation of neuroinflammatory pathways, which collectively contribute to neuroprotection and improved cognitive outcomes.33,65, 33,65

Exercise training also contributes to neuroprotection and neuroplasticity through the release of myokines and exerkines. These include irisin, cathepsin B, and fibroblast growth factor 21 (FGF21), among others, which have been shown to cross the blood-brain barrier and exert beneficial effects on brain health.66,67, 66,67 Irisin, for instance, has been linked to increased BDNF expression and enhanced synaptic plasticity in the hippocampus. 68

Finally, the pilot study conducted by Wang et al. 18 offers valuable perspectives on the potential cognitive benefits of IHE, although further validation and generalization of these promising findings are warranted. The observed improvements in overall cognitive performance, coupled with the simultaneous increase in ScO₂, CVC, and V_MCA indicate a potential link between IHE and improvements in cerebral blood flow and oxygenation. These physiological changes suggest a mechanism by which IHE may influence cognitive function, underscoring the significance of sufficient cerebral oxygen supply for optimal cognitive performance. Notably, these findings align with previous research, reinforcing the notion that IHE stands as an effective intervention for enhancing cerebral hemodynamics and circulation in the general population, holding therapeutic promise in the prevention of neurodegenerativediseases.27,69,70 , 27,69,70

The findings from our systematic review suggest that IHHT holds promise as an effective intervention for enhancing cognitive function in older adults with cognitive impairments, yielding enhancements in cognitive performance that are measurable through various cognitive tests. The improvements are more pronounced when IHHT is part of a multimodal regimen that includes physical training. 21 Additionally, there is evidence suggesting that IHHT may also impact cerebral hemodynamics, potentially providing neurophysiological mechanisms for the cognitive improvements observed 47 . These studies collectively highlight the therapeutic potential of IHHT combined with physical exercise in managing cognitive decline associated with aging and neurodegenerative diseases.21,47, 21,47

Limitations

While this systematic review offers valuable insights, it is important to note that it has some limitations that should be considered. The included studies in the review did not distinguish between males and females, potentially introducing a sex-related factor that could have influenced the outcomes. A limited number of studies have investigated the effects of IH on cognitive performance in healthy older adults.

While IHHT showed more promising effects on cognition compared to IHT, it is important to note that studies on cognition involving IHT are still somewhat limited. There is a lack of studies investigating the effects of IHHE on both cognitively and non-cognitively impaired older adults. Additionally, the scope of the included studies was confined to specific types of cognitive impairment, namely mild cognitive impairment, Alzheimer’s disease, and vascular dementia. Consequently, the findings may not be readily applicable to other forms of dementia, such as Lewy body dementia, or to individuals in more severe stages of Alzheimer’s disease. Furthermore, we observed a limited representation of ethnic diversity from various regions in the included studies, which may impact the generalizability of the findings.

In addition, a large proportion of the studies omitted the calculation of sample sizes which is a crucial aspect for enhancing the quality and transparency of their research. By incorporating this important step, researchers can improve the robustness and credibility of their findings. 71 Another limitation of our review is that we had to exclude two studies due to the unavailability of English texts (Russian language).

Conclusion and future prospects

This systematic review reveals that both IHT and IHE show improvements in cognitive functions and cerebral health-related outcomes, including ScO₂, V_MCA and CVC. Additionally, IHE showed an increase in ScO₂ only when used with cognitively impaired populations. However, IHT and IHHT had no significant effect on BDNF levels. IHHT demonstrated benefits in improving cognitive function, but this was only investigated in cognitively impaired populations; future studies need to test these effects on healthy older adults. Notably, there are no studies on IHHE in both cognitively and non-cognitively impaired older adults.

These enhancements can be attributed to cellular responses that promote neuroprotection and neuroplasticity, mechanisms that are crucial in countering age-related cognitive decline.

These responses include enhanced antioxidant defenses, anti-inflammatory mechanisms, improved mitochondrial function, and effective autophagy. Enhanced mitochondrial biogenesis and function improve neuronal survival, and ensure protein homeostasis, preventing the accumulation of misfolded proteins that can lead to neuronal death. Neural connections are reorganized and new ones are formed, which is essential for learning, memory, and recovery from injury. This process is supported by neurotrophic factors, which are upregulated through exercise, enhancing synaptic plasticity and cognitive function. Furthermore, myokines and exerkines, released during physical activity, play significant roles in these processes by crossing the blood-brain barrier and stimulating in their turn neurotrophic factors, highlighting the systemic benefits of regular exercise on brain health.

These findings underscore the potential of hypoxic training protocols not only as therapeutic strategies but also in their capacity to invoke biological processes that reinforce brain health. Consequently, this advocates for further research to refine and optimize hypoxic training protocols, aiming to maximize their therapeutic efficacy for age-related cognitive decline.

Future research should concentrate on standardizing IHT/IHE/IHHE/IHHT protocols and exploring their long-term cognitive effects, including the identification of induced neuroprotective biomarkers. Tailoring these interventions to individual cognitive baselines could enhance efficacy within elderly subgroups. Simultaneously, there is a need to investigate the synergistic effects of combining hypoxia protocols with physical exercises across various health statuses. The inclusion of diverse populations in these studies will ensure a more comprehensive understanding of these interventions’ potential in geriatric health across different races and ethnicities.

AUTHOR CONTRIBUTIONS

Ayoub Boulares (Conceptualization; Methodology; Project administration; Validation; Writing – original draft; Writing – review & editing); Aurélien Pichon (Supervision; Validation; Writing – original draft; Writing – review & editing); Corentin Faucher (Methodology; Writing – review & editing); Nicola Luigi Bragazzi (Formal analysis; Methodology; Writing – original draft; Writing – review & editing); Olivier Dupuy (Conceptualization; Methodology; Writing – original draft; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

The authors have no funding to report.

CONFLICT OF INTEREST

Nicola Luigi Bragazzi is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.

The other authors have no conflicts of interest to report.

DATA AVAILABILITY

The data employed in this systematic review are secondary and can be accessed through the articles cited throughout the review.

The supplementary material is available in the electronic version of this article: .

References

Oschwald

, Guye

, Liem

, et al. Brain structure and cognitive ability in healthy aging: a review on longitudinal correlated change. Rev Neurosci 2019; 31: 1–57.

Shin

J-H

. Dementia epidemiology fact sheet 2022. Ann Rehabil Med 2022; 46: 53–59.

Abraha

, Rimland

, Trotta

, et al. Systematic review of systematic reviews of non-pharmacological interventions to treat behavioural disturbances in older patients with dementia. The SENATOR-OnTop series. BMJ Open 2017; 7: e012759.

Chiang

. Obstructive sleep apnea and chronic intermittent hypoxia: a review. Chin J Physiol 2006; 49: 234–243.

Neubauer

. Invited review: Physiological and pathophysiological responses to intermittent hypoxia. J Appl Physiol 2001; 90: 1593–1599.

Zhang

, Zhao

, Li

, et al. Intermittent hypoxia conditioning: a potential multi-organ protective therapeutic strategy. Int J Med Sci 2023; 20: 1551–1561.

Timon

, Martinez-Guardado

and Brocherie

. Effects of intermittent normobaric hypoxia on health-related outcomes in healthy older adults: a systematic review. Sports Med - Open 2023; 9: 19.

Behrendt

, Bielitzki

, Behrens

, et al. Effects of intermittent hypoxia– hyperoxia on performance- and health-related outcomes in humans: a systematic review. Sports Med - Open 2022; 8: 70.

Glazachev

. Optimization of clinical application of interval hypoxic training. Biomed Eng 2013; 47: 134–137.

10.

Gonchar

and Mankovska

. Moderate hypoxia/hyperoxia attenuates acute hypoxia-induced oxidative damage and improves antioxidant defense in lung mitochondria. Acta Physiol Hung 2012; 99: 436–446.

11.

Sazontova

, Bolotova

, Bedareva

, et al. Adaptation to intermittent hypoxia/hyperoxia enhances efficiency of exercise training. In: Xi

and Serebrovskaya

(eds) Intermittent Hypoxia and Human Diseases. London: Springer, pp. 191–205.

12.

Zhang

, Chen

, Li

, et al. Hypoxia preconditioning attenuates lung injury after thoracoscopic lobectomy in patients with lung cancer: a prospective randomized controlled trial. BMC Anesthesiol 2019; 19: 209.

13.

Lyamina

, Lyamina

, Senchiknin

, et al. Normobaric hypoxia conditioning reduces blood pressure and normalizes nitric oxide synthesis in patients with arterial hypertension. J Hypertens 2011; 29: 2265–2272.

14.

Burtscher

, Pachinger

, Ehrenbourg

, et al. Intermittent hypoxia increases exercise tolerance in elderly men with and without coronary artery disease. Int J Cardiol 2004; 96: 247–254.

15.

Tin’kov

and Aksenov

. Effects of intermittent hypobaric hypoxia on blood lipid concentrations in male coronary heart disease patients. High Alt Med Biol 2002; 3: 277–282.

16.

Serebrovska

, Portnychenko

, Drevytska

, et al. Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression. Exp Biol Med (Maywood) 2017; 242: 1542–1552.

17.

Schega

, Peter

, Törpel

, et al. Effects of intermittent hypoxia on cognitive performance and quality of life in elderly adults: a pilot study. Gerontology 2013; 59: 316–323.

18.

Wang

, Shi

, Schenck

, et al. Intermittent hypoxia training for treating mild cognitive impairment: a pilot study. Am J Alzheimers Dis Other Demen 2020; 35: 1533317519896725.

19.

Dudnik

, Zagaynaya

, Glazachev

, et al. Intermittent hypoxia-hyperoxia conditioning improves cardiorespiratory fitness in older comorbid cardiac outpatients without hematological changes: a randomized controlled trial. High Alt Med Biol 2018; 19: 339–343.

20.

Glazachev

, Kopylov

, Susta

, et al. Adaptations following an intermittent hypoxia-hyperoxia training in coronary artery disease patients: a controlled study. Clin Cardiol 2017; 40: 370–376.

21.

Bayer

, Likar

, Pinter

, et al. Intermittent hypoxic-hyperoxic training on cognitive performance in geriatric patients. Alzheimers Dement (N Y) 2017; 3: 114–122.

22.

Bayer

, Likar

, Pinter

, et al. Effects of intermittent hypoxia-hyperoxia on mobility and perceived health in geriatric patients performing a multimodal training intervention: a randomized controlled trial. BMC Geriatr 2019; 19: 167.

23.

Cheng

, Yu

, Yan

, et al. Hypoxia-Inducible factor-1α target genes contribute to retinal neuroprotection. Front Cell Neurosci 2017; 11: 20.

24.

Direct transcriptional targets of HIF | Learn Science at Scitable, https://www.nature.com/scitable/content/directtranscriptional-targets-of-hif-33039/ (accessed 13 February 2024).

25.

Sies

and Jones

. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 2020; 21: 363–383.

26.

Leonard

, Kieran

, Howell

, et al. Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury. FASEB J 2006; 20: 2624–2626.

27.

Manukhina

, Downey

, Shi

, et al. Intermittent hypoxia training protects cerebrovascular function in Alzheimer’s disease. Exp Biol Med (Maywood) 2016; 241: 1351–1363.

28.

, Ru

and Wen

. NRF2, a transcription factor for stress response and beyond. Int J Mol Sci 2020; 21: 4777.

29.

Franceschi

, Bonafè

, Valensin

, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000; 908: 244–254.

30.

Harman

. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11: 298–300.

31.

Merelli

, Repetto

, Lazarowski

, et al. Hypoxia, oxidative stress, and inflammation: three faces of neurodegenerative diseases. J Alzheimers Dis. 2021; 82: S109–S126.

32.

Streck

, Czapski

, Gonçalves da Silva

. Neurodegeneration, mitochondrial dysfunction, and oxidative stress. Oxid Med Cell Longev 2013;826046.

33.

Burtscher

, Mallet

, Burtscher

, et al.

Hypoxia and brain aging: Neurodegeneration or neuroprotection?

Ageing Res Rev 2021; 68: 101343.

34.

Marques-Aleixo

, Santos-Alves

, Balça

, et al. Physical exercise improves brain cortex and cerebellum mitochondrial bioenergetics and alters apoptotic, dynamic and auto(mito)phagy markers. Neuroscience 2015; 301: 480–495.

35.

Lafenetre

, Leske

, Wahle

, et al. The beneficial effects of physical activity on impaired adult neurogenesis and cognitive performance. Front Neurosci 2011; 5: 51.

36.

Bernardo

, Beleza

, Rizo-Roca

, et al. Physical exercise mitigates behavioral impairments in a rat model of sporadic Alzheimer’s disease. Behav Brain Res 2020; 379: 112358.

37.

Page

, McKenzie

, Bossuyt

, et al. The PRISMA statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol 2021; 134: 178–189.

38.

Downs

and Black

. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998; 52: 377–384.

39.

Davies

, Orr

, Halaki

, et al. Effect of training leading to repetition failure on muscular strength: a systematic review and meta-analysis. Sports Med 2016; 46: 487–502.

40.

Samoocha

, Bruinvels

, Elbers

, et al. Effectiveness of web-based interventions on patient empowerment: a systematic review and meta-analysis. J Med Internet Res 2010; 12: e23.

41.

Singh Chawla

. How reliable is this research? Tool flags papers discussed on PubPeer. Nature 2024; 629: 271–272.

42.

Thorp

, Vinson

and Yeston

. Strengthening the scientific record. Science 2023; 380: 13.

43.

Behrendt

, Altorjay

A-C

, Bielitzki

, et al. Influence of acute and chronic intermittent hypoxic-hyperoxic exposure prior to aerobic exercise on cardiovascular risk factors in geriatric patients— a randomized controlled trial. Front Physiol 2022; 13: 1043536.

44.

Schega

, Peter

, Brigadski

, et al. Effect of intermittent normobaric hypoxia on aerobic capacity and cognitive function in older people. J Sci Med Sport 2016; 19: 941–945.

45.

Behrendt

, Quisilima

, Bielitzki

, et al. Brain-derived neurotrophic factor and inflammatory biomarkers are unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure in geriatric patients: a randomized controlled trial. Ann Med 2024; 56: 2304650.

46.

Liu

, Chen

, Kline

, et al. Reduced cerebrovascular and cardioventilatory responses to intermittent hypoxia in elderly. Respir Physiol Neurobiol 2020; 271: 103306.

47.

Behrendt

, Bielitzki

, Behrens

, et al. Effects of intermittent hypoxia-hyperoxia exposure prior to aerobic cycling exercise on physical and cognitive performance in geriatric patients-a randomized controlled trial. Front Physiol 2022; 13: 899096.

48.

Serebrovska

, Serebrovska

, Kholin

, et al. Intermittent hypoxia-hyperoxia training improves cognitive function and decreases circulating biomarkers of Alzheimer’s disease in patients with mild cognitive impairment: a pilot study. Int J Mol Sci 2019; 20: 5405.

49.

Serebrovska

, Xi

, Tumanovska

, et al. Response of circulating inflammatory markers to intermittent hypoxia-hyperoxia training in healthy elderly people and patients with mild cognitive impairment. Life (Basel) 2022; 12: 432.

50.

Ciesielska

, Sokołowski

, Mazur

, et al. Is the Montreal Cognitive Assessment (MoCA) test better suited than the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) detection among people aged over 60? Meta-analysis. Psychiatr Pol 2016; 50: 1039–1052.

51.

Jia

, Wang

, Huang

, et al. A comparison of the Mini-Mental State Examination (MMSE) with the Montreal Cognitive Assessment (MoCA) for mild cognitive impairment screening in Chinese middle-aged and older population: a cross-sectional study. BMC Psychiatry 2021; 21: 485.

52.

Wei

, Chen

, Hou

, et al. Age-related alterations in brain perfusion, venous oxygenation, and oxygen metabolic rate of mice: a 17-month longitudinal MRI study. Front Neurol 2020; 11: 559.

53.

Jung

, Simpkins

, Wilson

, et al. Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats. J Appl Physiol 2008; 105: 510–517.

54.

Zhu

X-H

, Yan

H-C

, Zhang

, et al. Intermittent hypoxia promotes hippocampal neurogenesis and produces antidepressant-like effects in adult rats. J Neurosci 2010; 30: 12653–12663.

55.

Paltsyn

, Manukhina

, Goryacheva

, et al.

Intermittent hypoxia stimulates formation of binuclear neurons in brain cortex- a role of cell fusion in neuroprotection?

Exp Biol Med (Maywood) 2014; 239: 595–600.

56.

Navarrete-Opazo

and Mitchell

. Therapeutic potential of intermittent hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol 2014; 307: R1181–1197.

57.

Manukhina

, Goryacheva

, Barskov

, et al. Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer’s disease by adaptation to hypoxia. Neurosci Behav Physiol 2010; 40: 737–743.

58.

Burtscher

, Maglione

, Di Pardo

, et al. A rationale for hypoxic and chemical conditioning in Huntington’s disease. Int J Mol Sci 2021; 22: 582.

59.

Dinoff

, Herrmann

, Swardfager

, et al. The effect of acute exercise on blood concentrations of brain-derived neurotrophic factor in healthy adults: a meta-analysis. Eur J Neurosci 2017; 46: 1635–1646.

60.

Rojas Vega

, Strüder

, Vera Wahrmann

, et al. Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans. Brain Res 2006; 1121: 59–65.

61.

Behrendt

, Kirschnick

, Kröger

, et al. Comparison of the effects of open vs. closed skill exercise on the acute and chronic BDNF, IGF-1 and IL-6 response in older healthy adults. BMC Neurosci 2021; 22: 71.

62.

Knaepen

, Goekint

, Heyman

, et al. Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects. Sports Med 2010; 40: 765–801.

63.

Timon

, González-Custodio

, Vasquez-Bonilla

, et al. Intermittent hypoxia as a therapeutic tool to improve health parameters in older adults. Int J Environ Res Public Health 2022; 19: 5339.

64.

Park

and Poo

. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 2013; 14: 7–23.

65.

Hochachka

, Buck

, Doll

, et al. Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Natl Acad Sci U S A 1996; 93: 9493–9498.

66.

Fiuza-Luces

, Garatachea

, Berger

, et al. Exercise is the real polypill. Physiology (Bethesda) 2013; 28: 330–358.

67.

Chow

, Gerszten

, Taylor

, et al. Exerkines in health, resilience and disease. Nat Rev Endocrinol 2022; 18: 273–289.

68.

Wrann

, White

, Salogiannnis

, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab 2013; 18: 649.

69.

Zhang

, Zhou

, Cao

, et al. Preliminary intermittent hypoxia training alleviates the damage of sustained normobaric hypoxia on human hematological indexes and cerebral white matter. High Alt Med Biol 2022; 23: 273–283.

70.

, Zhang

, Chen

, et al. Effect of intermittent hypoxic training on hypoxia tolerance based on brain functional connectivity. Physiol Meas 2016; 37: 2299–2316.

71.

Wang

and Ji

. Sample size estimation in clinical research: from randomized controlled trials to observational studies. Chest 2020; 158: S12–S20.