Mild cognitive impairment (MCI) is a condition in which individuals demonstrate cognitive impairment with minimal impairment of instrumental activities of daily living (IADL) (Petersen et al., 2018). MCI is an intermediate state between normal cognition and dementia. Persons with MCI are at higher risk of progressing to dementia than age-matched controls, and the cumulative dementia incidence was 14.9% in individuals with MCI older than age 65 years followed for 2 years (Tangalos and Petersen, 2018). According to the 2018 American Academy of Neurology (AAN) guideline on MCI, MCI prevalence was 6.7% for ages 60–64, 8.4% for 65–69, 10.1% for 70–74, 14.8% for 75–79, and 25.2% for 80–84. Thus, there is significant public health value in identifying MCI early and intervening as soon as possible to prevent or postpone the transition from MCI to dementia.

To date, pharmacological interventions have been suboptimal in slowing the cognitive decline and preventing the transition of patients with MCI to dementia (Andrieu et al., 2015; Petersen et al., 2018). Therefore, there are growing interests in the effectiveness of non-pharmacological interventions. Cognitive training is an increasingly popular, non-pharmacological intervention for improving cognitive functioning in neurodegenerative diseases and healthy aging (Van Balkom et al., 2020). Cognitive training involves cognitive exercises that target specific cognitive abilities and neural networks to potentially improve cognitive functioning through neuroplasticity (D’Antonio et al., 2019). Systematic reviews show evidence that cognitive training can be effective in improving various aspects of objective cognitive functioning; memory performance, executive functioning, processing speed, attention, fluid intelligence, and subjective cognitive performance (Reijnders et al., 2013; Hill et al., 2017; Sherman et al., 2017). The 2018 American Academy of Neurology (AAN) guideline on MCI recommended cognitive training as a non-medication approach to improve cognitive function (Petersen et al., 2018).

Combining cognitive training with other interventions might greatly increase the likelihood of cognitive benefit. Recent studies have indicated that there appears to be merit in multicomponent composite approaches involving cognitive training and other interventions such as physical activity (Karssemeijer et al., 2017; Gavelin et al., 2021), aerobic exercise (Mirza and Yaqoob, 2018; Park H. et al., 2019), transcranial direct current stimulation (Lawrence et al., 2018) and risk factor modification (Xu et al., 2020) for improving cognitive performance in older adults with MCI, possibly offering more benefit than a single-bout intervention approach. A meta-analysis showed that multicomponent and multidomain forms of intervention might prompt recruitment of alternate neural processes as well as support primary networks to meet task demands simultaneously (Sherman et al., 2017).

Acupressure, a non-invasive technique, involves the use of fingers, thumbs, knuckles, or an appropriate acupressure tool to apply pressure to the acupoints (Schlaeger et al., 2017). A 1-year randomized controlled trial conducted by Zeng et al. (2016) showed that acupressure improved the older adults’ sleep quality as well as cognitive functions. McFadden et al. (2011) found that acupressure was associated with enhanced working memory function in participants suffering from cognitive impairment following traumatic brain injury. According to Traditional Chinese Medicine (TCM), acupressure treatment can stimulate the related meridians and reproduce an effect usually defined as “De Qi” to correct the imbalance of Qi in the body of patients with MCI (Smith et al., 2020). From the biomedical perspective, acupressure may stimulate the nervous system and positively modulate the regulation of serum cortisol, serotonin, endorphin, and the activity of different neurotransmitters (Moyer et al., 2011; Hmwe et al., 2015; Zullo et al., 2020). There are no reports of adverse reactions or sequelae from the use of any acupressure techniques, thus acupressure is a safe therapy. So far, the effect of acupressure on cognitive functions of subjects with MCI has not been reported.

Acupressure and cognitive training are two promising non-pharmacological interventions. Acupressure may stimulate the nervous system and alter physiological functions since the majority of acupressure points are either connected to, or located near neural structures (Zullo et al., 2017), while cognitive training improves selective brain function intensively (De Marco et al., 2018; Park J. et al., 2019). Hence, combined acupressure and cognitive training may yield a synergistic effect on cognition by complementary strengthening of different neural functions. However, the efficacy of the combined intervention compared to a single acupressure or a single cognitive training intervention remains unclear in older adults with MCI. Given the uneven distribution of medical resources worldwide and the vast elderly population, feasible, safe, and cost-effective interventions are required to intervene MCI. Therefore, this study aimed to evaluate the effects of acupressure and cognitive training, both individual and combined, on cognitive functions of older adults with MCI. Two hypotheses derived from the aim of this study: (i) acupressure, as well as cognitive training, would have beneficial effect for cognitive functions of older adults with MCI, and (ii) the combined effect of acupressure and cognitive training would outperform acupressure or cognitive training alone in improving cognitive performance of older adults with MCI.

Our findings are consistent with a growing body of research demonstrating the beneficial effects of cognitive training for patients with MCI (Feng et al., 2018; Li et al., 2019; Zhang et al., 2019b). Previous findings suggest that memory deficits in patients with MCI may emerge through a combined “loss” of medial temporal and frontoparietal functioning (Munro et al., 2015; Schnellbächer et al., 2020; Tang et al., 2021). Cognitive training is accompanied by significant and highly increases in activation in regions associated with the frontoparietal cognitive control network bilaterally (Hampstead et al., 2017; Raichlen et al., 2020; Simon et al., 2020). A systematic review (Miotto et al., 2018) indicated the association of cognitive improvement after cognitive training with both restorative (i.e., re-engaging the “typical” neural networks) and compensatory (i.e., engaging alternative neural networks that are not “typically” engaged) mechanisms.

This study also found that acupressure was comparably effective compared to cognitive training on improving cognitive functions of older adults with MCI. Acupressure is one of the major modalities of Traditional Chinese Medicine (TCM). TCM describes a state of health maintained by a balance of energy or Qi in the body (Xutian et al., 2009). According to TCM, Qi-Deficiency is a common feature in older adults with MCI (Deng et al., 2021). Acupressure treatment can stimulate the related meridians and reproduce an effect usually defined as “De Qi” to correct the imbalance of Qi in the body (Smith et al., 2020). From the perspective of modern medicine, it is suggested that acupressure may stimulate the nervous system since the fascial tissue of elderly people is susceptible to hands-on based conservative treatments (Zullo et al., 2020), and acupressure points are either connected to, or located near neural structures (Zullo et al., 2017). Manual stimulation of acupressure points has been shown to increase the production of serotonin and endorphin, as well as to positively modulate the regulation of serum cortisol and the activity of different neurotransmitters (Moyer et al., 2011; Hmwe et al., 2015; Zeng et al., 2016). Moreover, recent research highlight that manipulations may also influence the cytokine system and other pro-inflammatory molecules as well as cortical plasticity (Witzel et al., 2011; Yeh et al., 2017; Chang et al., 2020), which are known to be part of the pathomechanisms of neurodegenerative diseases (Bagyinszky et al., 2017; Meder et al., 2021).

Acupressure is non-invasive and can be performed by non-professionals at any time without the limitation of field or equipment. Once mastered, it can be practiced for life. Thus, acupressure may serve as a cost-effective, non-pharmacologic, complementary treatment for older adults with MCI. During this study, many participants reported significant improvements in overall health status through acupressure, such as sleep quality and emotion. Therefore, older adults are more likely to accept it and follow it for a long time.

Based on this study, we observed clear benefits for simultaneous acupressure and cognitive training over and above each modality alone, on the cognitive functions of older adults with MCI. Cognitive training is a process of active learning, which can fully tap the brain potential of the MCI patients and reconstruct the structure and function of the central nervous system (Sherman et al., 2017; Miotto et al., 2018; Hampstead et al., 2019). Beyond that, through the physical stimulation of acupressure at special acupoints, the cerebral blood flow of the corresponding cortex can be increased, the excitability of the nervous system can be regulated, the metabolism of the body can be increased, the immune function can be improved, and the brain atrophy can be prevented or slowed down (Yuan et al., 2019). Thus, the combination of cognitive training and acupressure combines their respective advantages and plays a joint role in promoting the benign changes in brain structure and function. However, from the evidence available, we have not come to a conclusion yet whether the combined effect is additive or synergistic. We did not collect brain imaging scans as part of this RCT and cannot address aspects of brain structure, function, and connectivity that underlie improvements in cognitive performance in response to simultaneous vs. individual intervening modalities. Determining how these combined acupressure and cognitive training interact should be a key element of future work.

The results of the present study showed that the improvements in cognition of participants in experimental groups emerged markedly in the first 3 months. At present, there is no unified length or duration of cognitive training or acupressure recommended for the treatment of MCI. Systematic reviews of cognitive training for MCI showed that the dose and duration of the cognitive training intervention was variable, with the total length of training ranging from 4 to 80 h and the duration of training from 2 to 24 weeks (Gates et al., 2019; Zhang et al., 2019a). In terms of acupressure, the evidence is very limited by now since there are few studies on the treatment of MCI by acupressure. Hence, more normative recommendation for appropriate length and duration of the interventions, as well as the frequency, needs to be developed in the future.

In the present study, cognitive training and acupressure can be feasibly performed by trained older adults with MCI. Self-administered training programs are essential. Not only do some older adults have limited time or ability to attend training programs away from their homes, but training programs require involvement by trainers who may not always be available or affordable (Bailey et al., 2010). Thus, widespread dissemination of a training technique will require self-administration by older adults. Results of previous studies support the efficacy of self-administered cognitive training in reliably improving cognitive and functional abilities, as well as self-efficacy (West et al., 2008), in normal older adults (Rizkalla, 2018) or individuals with MCI (Han et al., 2017). A systematic review of self-acupressure suggests that self-administered acupressure shows promise to alleviate the symptoms of various health problems, including allergic disease, cancer, respiratory disease, dysmenorrhea, perceived stress, insomnia, and sleep disturbances (Song et al., 2015). Moreover, cognitive training and acupressure can be self-administered without expensive costs, irrespective of geographic location, clinic and/or therapist availability. However, whilst the findings support the potential for self-administered cognitive training and acupressure as treatment strategy, they also underscore the importance of compliance monitoring in the delivery of the training, which needs to be carefully considered and planned before studies begin. Overall, under effective monitoring, self-administered training might be an innovative and effective strategy for older adults that remain independent and actively engaged in their brain health.

The present study had several limitations. First, the follow-up effect was not evaluated to detect the long-term sustainable efficacy of acupressure and cognitive training. Further researches with follow-up effect evaluation are therefore recommended. Second, although subjects who had suffered from diseases like depression or severe sleep disorder which could potentially compromise their cognition were excluded as eligible participants, there still might be some confounding factors that influenced the intervention effects during the trial. Third, the assessment of cognitive functioning was limited in this study, therefore more complete measurement tools and the consideration of including measurement of other variables such as quality of life were recommended for future studies. Fourth, the participants were not blind to their interventions, which may have led to a Hawthorne effect-like influence on the experimental groups. In addition, social interactions during the training might have positive cognitive effects on the participants. Thus, the lack of an active control which could replicate the social interactions was also a limitation of this study and need to be addressed in future studies.

This study indicated that acupressure and cognitive training both could improve the cognitive functions of older adults with MCI, and when used together, the effects were enhanced. To the best of our knowledge, this is the first randomized controlled trial to evaluate the combined effect of acupressure and cognitive training on cognitive functions of older adults with MCI. Acupressure is safe, cost-effective and can be implemented by non-professionals. Thus, it may serve as a complementary intervention to improve cognitive functions and prevent dementia in community-dwelling older people, especially for those with MCI. Acupressure can be combined with other interventions such as cognitive training to achieve better improvements on cognitive functions.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by China Ethics Committee of Registering Clinical Trials and Central South University. The patients/participants provided their written informed consent to participate in this study.

JS: methodology, project administration, investigation, and writing—original draft preparation. HZ: conceptualization, supervision, and writing—reviewing and editing. LP: investigation and formal analysis. XW: investigation and formal analysis. ML: investigation. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.