Acetylcholine is associated with memory, learning, attention, and other essential aspects of cognition (Hampel et al., 2018). Aging and AD are associated with cholinergic neuron loss (Terry and Buccafusco, 2003; Haam and Yakel, 2017). Cholinesterase inhibitors (ChEIs) block acetylcholinesterase, thereby delaying the breakdown of acetylcholine and enhancing cholinergic neurotransmission. ChEIs, including donepezil, galantamine, and rivastigmine, have been approved for treating AD (Oh and Rabins, 2019). Donepezil is a non-competitive acetylcholinesterase inhibitor that was approved in 1996. Donepezil administration for 12 or 24 weeks has a small beneficial improvement on cognition in AD. The beneficial effects of 10 or 23 mg daily are slightly larger than 5 mg daily. However, the rates of withdrawal and adverse events are higher with higher doses (Birks and Harvey, 2018). Rivastigmine can inhibit both acetylcholinesterase and butyrylcholinesterase and was approved in 2000. Rivastigmine could also improve cognitive function in AD (Birks and Grimley Evans, 2015). Galantamine is a competitive inhibitor of acetylcholinesterase. Administration with 16–40 mg galantamine daily for 8–28 weeks can significantly enhance cognitive function (Jiang et al., 2015). Although there are slight variations in the mode of actions, there are no differences in their efficacy for cognitive improvement in AD (Birks, 2006). A network meta-analysis assessed the efficacy of cholinesterase inhibitor for vascular dementia and other vascular cognitive impairments, donepezil, and galantamine were found to slightly improve cognition, although the effects were not clinically significant. The evidence for rivastigmine is less certain (Battle et al., 2021). A meta-analysis evaluating the clinical benefit of ChEIs for MCI has been published in 2019 by Matsunaga et al. (2019). That study included 14 randomized controlled trials (RCTs) with 5,278 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., 2019; Oh and Rabins, 2019). New versions of ChEIs such as octohydroaminoacridine and AD-35 are in development (Cummings et al., 2021).

Besides cholinesterase inhibitors, memantine, a low-affinity NMDA receptor antagonist, has also been approved for treating AD (Huang and Mucke, 2012). 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., 2007; McShane et al., 2019). Currently, SAGE-718, another NMDA receptor positive allosteric modulator, is in Phase II clinical trial (Cummings et al., 2021).

Diabetes is another risk factor for dementia, and diabetes increase a 1.5–2 times higher risk of dementia (Areosa Sastre et al., 2017). 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., 2019; Erichsen et al., 2021).

Cerebrolysin is a mixture of neuropeptide and amino acids produced by the enzymatic breakdown of pig’s brain tissue, which acts as endogenous neurotrophic factors (Cui et al., 2019). Currently, cerebrolysin is used as the treatment for dementia in Europe and Asia (Cui et al., 2019; Gavrilova and Alvarez, 2021). In a meta-analysis, cerebrolysin was suggested to have beneficial effects on cognitive function in mild-to-moderate AD (Gauthier et al., 2015). The beneficial effect of cerebrolysin on cognitive function was also found in vascular dementia (Guekht et al., 2011). Alvarez et al. (2011) compared cerebrolysin and donepezil, and found that cerebrolysin was as effective as donepezil in cognitive improvement, and the combinational therapy had better cognitive performance than single-drug treatment. 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, 2021; van Bokhoven et al., 2021). No cognitive enhancing agent for AD has been recently approved for cognitive improvement in AD (Cummings, 2021; van Bokhoven et al., 2021). 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., 2021).

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., 2021). Stimulants such as amphetamine and methylphenidate were reported to improve executive function and memory in healthy adult (Smith and Farah, 2011; Ilieva et al., 2015). 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, 2015; Farah, 2015). However, their cognitive enhancing effect and safety on elder adults are still needed investigation. What’s more, these drugs are often misused and have abuse potential, which should be paid with more caution (Buccafusco, 2009; Milić et al., 2021).

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., 2020). 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., 2019). The difficulty of training tasks should be adjusted according to participants’ performance, which is particularly feasible when using computerized cognitive training. Cognitive stimulation involves non-specific engagement in activities for improving cognitive status (Bahar-Fuchs et al., 2019). Cognitive rehabilitation could achieve or preserve optimal levels of functioning in daily life (Gavelin et al., 2020). 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., 2019). 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., 2019). Hu et al. included both MCI and dementia patients with computerized cognitive training in a systematic review in 2021. 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., 2021). 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., 2012). 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., 2019). They both work by modulating synaptic efficacy and neural circuit and have been used in clinical practice.

Nutrition is an important factor that contributes to healthy aging. Adopting a healthier diet may be beneficial to cognition (Jennings et al., 2020). World Health Organization (2019) has advocated a healthy diet to reduce the risk of cognitive decline and/or dementia. 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., 2018). Dietary patterns were also suggested to be protective for brain health in elderly (Scarmeas et al., 2018; Power et al., 2019; Flanagan et al., 2020). The Mediterranean diet was the most extensively studied dietary pattern (Chen et al., 2019). 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., 2019). High adherence to the Mediterranean diet is associated with better global cognition and memory has been reported by meta-analysis (Coelho-Júnior et al., 2021). However, whether it could reduce the risk of developing MCI or dementia is still conflicted (Coelho-Júnior et al., 2021; García-Casares et al., 2021). 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, 2022). 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., 2018; Willyard, 2021). Gut microbiota is found to be associated with emotion, cognition, and social behavior (Sarkar et al., 2018). 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., 2021). 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., 2021). 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, 2014). Several meta-analyses analyzed the effects of exercise on cognition, focused predominantly on aerobic exercise (Jia et al., 2019; Sanders et al., 2019; López-Ortiz et al., 2021). Angevaren et al. (2008) performed a Cochrane review in older people without known cognitive impairment. 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., 2020). 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., 2019).

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., 2020). Another meta-analysis involving both healthy and MCI old adults also found dance enhanced global cognitive function and executive function (Hewston et al., 2021). 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, 2019). 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., 2018). 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., 2015). 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., 2021). 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., 2017). 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., 2021). Gavelin et al. (2021) reported that combined physical and cognitive training had a small beneficial effect on overall cognitive function in elder adults. Nutrition combined with physical exercise interventions could also improve global cognitive function in the elderly population (Liu et al., 2021).