That study included 14 randomized controlled trials RCTs with 5, subjects, where 6 studies involved donepezil, 4 involved galantamine, and 4 involved rivastigmine.

The results found that ChEIs did not improve cognitive function in MCI adults, however, ChEIs significantly slowed down the progression of dementia. As there are higher incidences of discontinuation due to adverse events, including nausea, vomiting, abnormal dreams, diarrhea, dizziness, bradyarrhythmia, syncope, and weight loss, ChEIs are not recommended for improving MCI Matsunaga et al.

New versions of ChEIs such as octohydroaminoacridine and AD are in development Cummings et al. Besides cholinesterase inhibitors, memantine, a low-affinity NMDA receptor antagonist, has also been approved for treating AD Huang and Mucke, In a Cochrane review, the clinical benefit of memantine was found in moderate-to-severe AD.

However, there was no clinical benefit of memantine for mild AD. Whether a long duration of memantine administration is beneficial for mild AD needs to be assessed. There is limited evidence of memantine for MCI and other causes of dementia Ferris et al. Currently, SAGE, another NMDA receptor positive allosteric modulator, is in Phase II clinical trial Cummings et al.

Diabetes is another risk factor for dementia, and diabetes increase a 1. Association between aging, dementia with disruption of insulin receptor signaling has been reported, insulin resistance has also been proposed as a mechanism for cognitive impairment.

Restoration of insulin signaling in the brain can be a potential way to improve cognition Boccardi et al. Intranasal administration of insulin can increase insulin levels in the central nervous system de la Monte, ; Erichsen et al.

Previous studies demonstrated that intranasal insulin had potentially beneficial effects on cognitive functions Reger et al. Acute intranasal insulin 20 IU treatment facilitates verbal memory in the elderly with MCI or AD, and these effects were stronger for patients without the APOE-epsilon4 allele Reger et al.

Craft et al. These findings indicate the potential beneficial effect of insulin on cognitive decline. Metformin is a first-line antihyperglycemic drug and works by increasing insulin sensitivity in peripheral tissues and suppressing hepatic gluconeogenesis Boccardi et al.

Although a meta-analysis of 6 cohort studies has shown metformin might reduce the incidence of dementia in diabetic patients Campbell et al. In a pilot randomized controlled trial with 80 MCI adults, metformin was found to increase verbal memory. Metformin was tolerated by Another study found that metformin administration for 8 weeks was associated with improved executive functioning in patients with MCI or mild dementia Koenig et al.

Currently, cerebrolysin is used as the treatment for dementia in Europe and Asia Cui et al. In a meta-analysis, cerebrolysin was suggested to have beneficial effects on cognitive function in mild-to-moderate AD Gauthier et al.

The beneficial effect of cerebrolysin on cognitive function was also found in vascular dementia Guekht et al. Alvarez et al.

In addition, whether cerebrolysin administration has a beneficial effect on cognitive function in cognitive healthy aging adults and in patients with MCI is still inconclusive, and whether cerebrolysin administration can delay the progression of dementia also needs to be further analyzed.

Drug development for AD has been challenging for the last two decades, although a variety of potential drug targets have been identified Cummings, ; van Bokhoven et al. No cognitive enhancing agent for AD has been recently approved for cognitive improvement in AD Cummings, ; van Bokhoven et al.

Table 2 shows the 13 drugs in clinical trials for the treatment of cognitive. Among them, one drug is in phase I trial, 6 drugs are in phase II trial, and 6 drugs are in phase III trial Cummings et al. Table 2. Phosphodiesterases PDEs are a superfamily including 11 isoforms that can catalyze second messengers cAMP and cGMP which have important roles in learning and memory Wu et al.

Almost all PDE isoforms are mostly expressed in the brain, especially in learning and memory regions Wu et al. PDEs inhibitors showed remarkable cognitive enhancement in preclinical studies Bruno et al. Vinpocetine is a classical PDE1 inhibitor and was discovered about 40 years ago Prickaerts et al.

Cilostazol is a selective PDE3 inhibitor. Cilostazol coadministration with donepezil or galantamine ameliorated cognitive decline efficiently in patients with moderate AD Arai and Takahashi, ; Hishikawa et al.

A cohort study recruiting participants found cilostazol treatment reduced the risk of developing dementia Tai et al. Roflumilast is a selective PDE4 Inhibitor. Roflumilast has completed the phase II trial as a cognition enhancer in healthy adults Van Duinen et al. PF is a selective PDE9A inhibitor.

Although PF was safe and well-tolerated, PF administration did not affect cognition when compared to the placebo Schwam et al. Besides ChEIs, mAChRs agonists and nAChRs agonists are being tested as the other two promising drug targets for cognitive improvement in AD.

Xanomeline, the first generation mAChRs agonist, has been demonstrated to improve cognition in a phase III trial.

However, due to the relatively low M1 receptor selectivity, xanomeline can lead to cholinergic adverse effects such as sweating, salivation, and gastrointestinal disturbances because of activating peripheral M2 and M3 mAChRs Scarpa et al. Unfortunately, later developed highly selective M1 mAChRs agonists, such as PF, MK, and PF, lead to cholinergic toxicity and behavioral convulsions Davoren et al.

nAChR agonists are less developed than mAChR agonists. There are several nAChR agonists developed for the cognitive improvement of AD patients in the past two decades, such as encenicline EVP and TC AZD Encenicline is well tolerated at single doses in healthy volunteers.

However, it was later suspended in the phase III trial due to serious gastrointestinal adverse effects in elderly patients Hoskin et al. TC is a selective α4β2 nAChR agonist Dunbar et al. A randomized placebo-controlled trial investigated its effects on cognition.

Compared to the placebo group, patients in TC 50 mg groups showed superior performance on attention and episodic memory Dunbar et al. In addition, a phase II trial analyzed its effect on cognitive function in MCI adults Cummings et al.

mAChRs agonist and nAChRs agonist could be promising treatments. However, there is still a long way to go before advancing them into the market Verma et al. Decreased release of dopamine and decreased expression of dopamine receptors are associated with age-related cognitive decline Volkow et al.

There is evidence of the involvement of dopamine in AD. Restoration of dopamine transmission can improve learning and memory of AD Guzmán-Ramos et al. In a trial of 60 participants, dopaminergic agonist piribedil administration improves global cognitive function in MCI patients Nagaraja and Jayashree, Koch et al.

Monoamine oxidase B MAO-B inhibition could increase the availability of dopamine Koch et al. In a phase II trial, Matthews et al. evaluated the potential benefit of rasagiline a selective MAO-B inhibitor in mild to moderate AD with 50 participants. The results showed rasagiline could improve brain metabolism as measured by fluorodeoxyglucose—positron emission tomography.

However, it did not affect globe cognitive function Matthews et al. Larger sample size trials are needed to evaluate the effect of dopaminergic stimulation on cognitive impairment. There were also drugs enhancing cognition in health adults in elderly, potential drugs including substances acting on neurotransmitters, hormones, transduction systems, and brain perfusion and metabolism Milić et al.

Stimulants such as amphetamine and methylphenidate were reported to improve executive function and memory in healthy adult Smith and Farah, ; Ilieva et al.

Modafinil is an FDA-approved eugeroic that could preserve alertness under conditions of sleep deprivation, through increases cortical catecholamine levels. Most studies found modafinil could enhances executive function, attention and learning and memory Battleday and Brem, ; Farah, However, their cognitive enhancing effect and safety on elder adults are still needed investigation.

A growing number of studies show that non-pharmacological interventions can enhance cognition in the last decade Gavelin et al. Non-pharmacological interventions covered a diverse range of intervention categories, including cognition-oriented treatments, non-invasive brain stimulation physical exercise, and lifestyle-related interventions Table 3.

Different clinical stages of cognitive impairment, from MCI to dementia, could all benefit from non-pharmacological treatments. Most non-pharmacological treatments have few adverse effects and can be combined with pharmacological treatments Sikkes et al.

Table 3. Evidence of non-pharmacological interventions for cognitive impairment in older adults. Cognition-oriented interventions, such as cognitive training, cognitive stimulation, and cognitive rehabilitation, are approaches for the prevention and treatment of cognitive decline in the elderly Gavelin et al.

They are in high availability, high accessibility, and low implementation costs. Cognitive training consists of repeated practices on standardized tasks aimed at improving or maintaining certain aspects of cognitive functions Bahar-Fuchs et al.

Cognitive stimulation involves non-specific engagement in activities for improving cognitive status Bahar-Fuchs et al. Cognitive rehabilitation could achieve or preserve optimal levels of functioning in daily life Gavelin et al.

Cognitive training has also been reported to have a small to moderate effect on global cognition and a moderate effect on verbal semantic fluency for mild to moderate dementia Bahar-Fuchs et al. Gates et al.

evaluated the effect of computerized cognitive training through a meta-analysis. However, no conclusion could be drawn on whether computerized cognitive training had a beneficial effect on cognitive function as the evidence was of low quality, and most of the results were imprecise Gates et al.

Hu et al. included both MCI and dementia patients with computerized cognitive training in a systematic review in They included 12 studies and found computerized cognitive training could improve general cognition, especially memory.

Subgroup analysis found computerized cognitive training on cognition for dementia was almost double for MCI Hu et al. Cognitive stimulation was also associated with improved cognitive function, self-reported quality of life, and communication and social interactions in dementia people Woods et al.

Although cognition-oriented treatments showed a positive effect on cognitive function, high-quality with larger sample size trials are needed, and further studies should be performed to address the potential benefits of longer-term interventions and their clinical significance.

As for non-invasive brain stimulation, transcranial electrical stimulation TES and transcranial magnetic stimulation TMS are the main techniques. Both techniques are safe and can be well tolerated without sedation or anesthesia Brunoni et al.

They both work by modulating synaptic efficacy and neural circuit and have been used in clinical practice. TES applicant a low-intensity 1—2 mA electric current to the brain via two electrodes anode and cathode , and transcranial direct current stimulation tDCS is the most studied.

The effects of tDCS are determined by the electrical current direction. Anodal tDCS increases neuronal activities by depolarizing the resting potential, while the cathodal tDCS inhibits neuronal activities by hyperpolarizing the resting potential Grimaldi et al. Cai et al. evaluated the effects of tDCS on cognition within mild to moderate AD patients through a meta-analysis.

The results revealed that tDCS could enhance cognitive function; in addition, only a single session of tDCS was effective, repeated sessions of tDCS were not effective, and lower current density 0.

Recently, Chu et al. analyzed the cognitive effects of TES on AD and MCI. After a 1-month follow-up, cathodal tDCS revealed larger therapeutic responses than anodal tDCS on general cognitive function.

Subgroup analysis only found patients with AD, but not MCI, significantly responded to cathodal tDCS Chu et al. Transcranial magnetic stimulation uses a magnetic field to induce action potentials.

The effects of TMS are determined by stimulation frequency. When the frequency is equal to or below 1 Hz, neural excitability is decreased. When the frequency is between 5 and 20 Hz, neural excitability is increased Cespón et al. TMS can use different stimulation patterns, including single-pulse TMS sTMS , double or paired pulse TMS dTMS , and repetitive TMS rTMS.

sTMS consists of the discharge of single pulses interleaved by at least 4 s periods off-stimulation, dTMS consists of the discharge of a test stimulus preceded by a conditioning stimulus, rTMS refers to more than two pulses delivered within a time interval of 2 s or less Valero-Cabré et al.

rTMS has been widely investigated in depression, and it has been approved by FDA for medication-resistant depression Iriarte and George, In recent years, rTMS has been considered as a promising intervention for cognitive improvement Iriarte and George, Two systematic reviews reported high frequency rTMS might show a moderate effect on cognition in AD and MCI patients Cheng et al.

However, the conclusion was limited by the small sample size of included studies. Larger RCTs and additional research are needed to identify the effect of TMS in the elderly with cognitive impairment.

Nutrition is an important factor that contributes to healthy aging. Adopting a healthier diet may be beneficial to cognition Jennings et al. Some, but not conclusive, evidence suggests that certain nutrients are protective of brain health in the elderly, including long-chain omega-3 fatty acids, vitamin B, vitamin D, selenium and etc.

Scarmeas et al. Dietary patterns were also suggested to be protective for brain health in elderly Scarmeas et al. The Mediterranean diet was the most extensively studied dietary pattern Chen et al.

It involves a high intake of vegetables, fruits, legumes, olive oil, whole grains, fish, low to moderate intake of dairy products, alcohol, and restrictions on red meat Power et al. High adherence to the Mediterranean diet is associated with better global cognition and memory has been reported by meta-analysis Coelho-Júnior et al.

However, whether it could reduce the risk of developing MCI or dementia is still conflicted Coelho-Júnior et al. The ketogenic diet was another specific diet, which might provide treatment benefits for AD patients. However, the current studies might be limited by small sample size, short-terms effects, and future studies should be further performed Hersant and Grossberg, The dietary intervention could be considered alongside other individualized interventions to improve cognition in elderly adults.

Interaction between gut microbes and the brain has received considerable attention in the past decade Martin et al.

Gut microbiota is found to be associated with emotion, cognition, and social behavior Sarkar et al. Probiotic intervention works by delivering specific strains of bacteria that increase the diversity and number of beneficial microbes, thereby altering the gut microbiota Eastwood et al.

Lv et al. evaluated the probiotics on cognition by meta-analysis, and they found that probiotic supplementations improved cognitive function. Subgroup analyses further found the enhanced effect existed only in people with impaired cognition.

Furthermore, a single strain was more effective than multiple strains Lv et al. Thus, probiotics have been suggested as an effective and accessible cognitive therapy; however, more randomized controlled clinical trials are needed for this conclusion.

Emerging evidence indicates exercise not only promotes physical health but also contributes to the preservation of cognition function. The mechanisms account for the neuroprotective effects of exercise on the brain include evaluated neurotrophic factor levels, increased synaptogenesis, improved vascularization, decreased systemic inflammation, and reduced abnormal protein deposition Kirk-Sanchez and McGough, Several meta-analyses analyzed the effects of exercise on cognition, focused predominantly on aerobic exercise Jia et al.

Angevaren et al. They found that aerobic exercise increased cognitive capacity, including motor function, cognitive speed, and visual attention. Another meta-analysis reported aerobic exercise attenuated the cognitive decline in MCI and dementia people, and found that working memory decline was significantly attenuated, and the effects on other domains of cognitive functions were unclear.

Moderate to high-intensity aerobic exercise had a better effect on cognition Law et al. Another meta-analysis examined the dose-response relationship and found shorter sessions and higher frequencies of exercise could generate a better cognitive effect Sanders et al.

Dancing intervention is another strategy, because it requires physical, cognitive, and social abilities, and thus been analyzed in many studies. In a recent meta-analysis in MCI populations, the results showed that dance had a small to moderate effect on cognitive function, such as attention, immediate and delayed recall, global cognition, and visuospatial ability Chan et al.

Another meta-analysis involving both healthy and MCI old adults also found dance enhanced global cognitive function and executive function Hewston et al. The positive effect of dance intervention on cognitive function in adults with AD was also confirmed in a systematic review Ruiz-Muelle and López-Rodríguez, Thus, dance has been suggested as an adjunct therapy for cognitive decline in the aging population.

As cognitive impairment is a complex, multifactorial disorder, multi-domain interventions have been suggested as a new strategy Kivipelto et al. In the last decades, 3 large clinical trials with multi-domain interventions FINGER, MAPT, and PreDIVA have been reported.

In the FINGER study, diet, exercise, cognitive training, and vascular risk monitoring were used to improve cognitive function in elderly people at risk for cognitive impairment Ngandu et al.

In the preDIVA study, a multi-domain intervention targeted vascular risk factors of smoking, unhealthy diet, physical inactivity, overweight, hypertension, dyslipidemia, and diabetes over 12 years was used.

However, it did not reduce dementia risk in older people Hoevenaar-Blom et al. In the MAPT trial, multi-domain intervention and Omega-3 PUFA supplementation were involved, and the results did not find significant effects on cognitive function Andrieu et al.

Despite these trials, several meta-analyses also analyzed multi-domain interventions on cognitive impairment. A Cochrane review found a small improvement in cognitive function with multi-domain interventions.

However, whether multi-domain interventions could decrease dementia incidences was uncertain Hafdi et al.

Gavelin et al. Nutrition combined with physical exercise interventions could also improve global cognitive function in the elderly population Liu et al. In conclusion, various pharmacological cholinesterase inhibitors, memantine, antidiabetic agents, probiotics, cerebrolysin and non-pharmacological interventions cognition-oriented treatments, non-invasive brain stimulation physical exercise, and lifestyle-related interventions have been proposed for cognitive impairment in older people.

Although a variety of new drug targets has been identified for cognition enhancement in older adults, the new drug is still in development. The existing potential drug targets should be further exploited, and discovering new drug targets could be a solution to the lack of effective drugs.

Most non-pharmacological interventions showed a small to moderate beneficial effect on cognitive function in cognitive impairment old people. Thus, combinations of pharmacological and non-pharmacological interventions or combinations of different types of non-pharmacological interventions may be more efficient in improving or preserving cognition.

YZ designed and edited the review. LC searched the data and drafted the review. JJ searched the data. All authors contributed to the article and approved the submitted version.

This study was partly supported by the National Natural Science Foundation of China No: , the Post Doctor Research Project of West China Hospital of Sichuan University No: 19HXBH , the China Postdoctoral Science Foundation No: M , and the Postdoctoral Research Project of Sichuan University No: SCU 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.

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Science , — Ferris, S. This argument and like-minded ones warrants investigation into whether this increased motivation would also ultimately augment well-being, as would more intrinsically motivated actions. An unintended consequence of pill-induced motivation on agency could be that intrinsic motivation to perform tasks generally declines and that pills become essential in motivating particular action, akin to a phenomenon of addiction.

Individuals might face a trade-off between greater attainments of outcomes and their sense of agency or self-efficacy. This could, in the end, reduce their well-being and autonomy by involuntarily increasing the motivation to work harder to realize unmotivating tasks Bavelier et al.

Currently, we do not have an in-depth understanding of the impact of enhancement technology on motivation and, more broadly, on agents users. However, we know that users of cognitive enhancers in the form of drugs tend to be motivated by increases in performance at work and in educational settings Sattler et al.

Furthermore, other studies have suggested that stress, lower-than-average performance, low intrinsic motivation, peer influence, procrastination, and other factors tend to increase the willingness for enhancer use Sattler et al.

Some users may also be self-medicating e. Motivations could be influenced by hyperbolic media discourse about cognitive enhancers Partridge et al. These findings speak to the centrality of human intents and motivations in debates about enhancement technology.

Unfortunately, a commonplace rhetorical strategy used in debates about enhancement is to minimize and sometimes dismiss the ethical importance of agency and agent motivations and, instead, bring attention to the consequences of actions.

Some proponents of moral enhancement, for example, claim without regard for the methods of enhancement and their differences or their potential side effects on agency that enhancement is essentially necessary for the end-goal of human well-being Savulescu, This strategy relies on a narrow understanding of what brings happiness and fulfilment to flourishing individuals Yaden et al.

However, other scholars take the opposite route and tend to boil down the ethics of enhancement only to its motivational aspects such that the outcomes do not seem to matter Sandel, This idea is embedded in several legal traditions including Anglo-American criminal law.

For example, the doctrine of mens rea guilty mind is part of the evaluation of the criminal responsibility of someone who has committed a criminal act. Likewise, people are usually interested in what is revealed about the person and their dispositions through their acts, and this is well-reflected in ethics theories that focus on agent characteristics MacIntyre, In this sense, cognitive enhancement is often viewed negatively because it suggests unvirtuous behavior Sandel, Public opinion, as well as ethical analysis, may come up with different justifications or condemnations regarding various motives, and this might guide reactions towards the user, demands regarding policies, and user behavior.

Furthermore, motivations to enhance need to be examined more carefully in light of their actual contribution to flourishing. Further examination of the motivations of those using cognitive enhancement, as well as the effects of cognitive enhancement on human motivation, is crucial from the standpoint of human psychology, sociology, and behavioral science.

Agent motivation and other factors should also be examined in the case of addiction, which may impair agency itself both self-attributed agency and agency attributed by others , as well as the ability to form and act on motivations.

Some of this research could be accomplished by studies in behavioral neuroscience focusing on the mechanisms and neural pathways of different types of motivation, so that concrete and consequential differences between forms of motivation and their potential consequences can be pinpointed.

Psychological studies could assess whether the intuitive notion that self-satisfaction is valuable applies to the case of cognitive enhancement and whether individuals using cognitive enhancement get the same sense of self-satisfaction from accomplishments as those who do not use it.

Other studies could further establish the importance of social factors, such as perceptions of moral situations given agent intentions. Potential effects of cognitive enhancement on human motivation need to be investigated to inform enlightened and rational policy decisions.

Experimental studies have been used to assess, for example, the impact of incentives on intrinsic motivation in many different contexts; although research ethics need to be carefully considered, such studies could be conducted in the context of cognitive enhancement and its effect on task involvement and intrinsic, as well as extrinsic, motivation to work on target tasks.

Additionally, large-scale longitudinal survey studies may offer opportunities to prospectively assess the impact of cognitive enhancers on those who have started or will start using them and the relationships between motivations for their use and the lived stress, social and economic pressures, culturally formed framings, and goals of potential users.

Further, interview-based and narrative social science research could help generate a deeper understanding of the impact of cognitive enhancers on actual users in comparison to non-users, while taking into account different values, orientations, and cultural backgrounds Groeneveld et al.

See Table 3 for suggestions for research on agency and agent user motivations. Research has provided some understanding of the motivations an individual may have for using cognitive enhancers, while mechanisms behind personal and situational drivers and hurdles, as well as their interplay, are still far from being sufficiently understood Sattler, ; Sattler et al.

For the testing of causal hypotheses, experimental and longitudinal research is the medium of choice. However, assessing such motivations in situ might be difficult. Moreover, we have a very incomplete understanding of the effects of cognitive enhancers on human motivations. Shedding light on these matters may either alleviate or bolster worries that cognitive enhancers will radically change the structure of human motivation and thwart ideals of human excellence and achievement.

Thus, effects on human motivation should not be presumed or discounted; the possibility that cognitive enhancement may be found to, for example, have no significant effect on motivational or other factors, should not preclude the need to test out whether this is the case empirically.

The growth of biotechnology and neuroscience yields numerous possibilities for the development of cognitive enhancement. So far, debates about these possibilities involve important claims about the psychological and social outcomes of enhancement consequences , the importance of enhancement methods used to attain a particular goal deeds , and the role of agency and agent user motivations.

These claims often stand as assumptions because they have not been sufficiently investigated. Yet, they are extremely important according to the ADC model that we have used as a heuristic to describe the ethical dimensions of cognitive enhancement.

We have argued for 1 the study of a broad range of social and psychological outcomes associated with cognitive enhancers in addition to biological and health outcomes ; 2 investigation into the importance of the specific enhancement methods used, as they may have different social and psychological implications; and 3 greater consideration of agency and the role of agent motivation and its relationship to user well-being.

These three components should not be investigated in isolation; their mutual dependency must be fully considered if a more realistic and comprehensive picture is sought. Importantly, regardless of study design, rigorous and scientific analyses must be based on open-mindedness about aspects of and arguments about cognitive enhancement regarding outcomes, deeds, and agent motivations — not only those which support a certain view or those valued in a given research protocol.

An analysis based only on a priori favorable or unfavorable opinions about these aspects can succumb to biases e. Extensive research into these aspects is imperative if we are to assess the ethics of the non- use of cognitive enhancers in an evidence-based and integrative manner and inform future policy making as well as technology development.

Defendable and rational policies concerning cognitive enhancement need to rely on strong and objective evidence exposing all aspects of cognitive enhancement, including its biological, legal, social, and psychological aspects. Eliana Neophytou, Laurie A.

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