Therapeutic approaches for improving cognitive function in the aging brain

Abstract

The rapid aging of populations around the world has become an unprecedented challenge. Aging is associated with cognitive impairment, including dementia and mild cognitive impairment. Successful drug development for improving or maintaining cognition in the elderly is critically important. Although 4 drugs for improving cognition in Alzheimer’s disease have been approved, a variety of potential drugs targeting age-related cognitive impairment are still in development. In addition, non-pharmacological interventions, including cognition-oriented treatments, non-invasive brain stimulation physical exercise, and lifestyle-related interventions, have also been suggested as cognitive enhancers in the last decade. In this paper, we reviewed the recent evidence of pharmacological and non-pharmacological interventions aimed at improving or maintaining cognition in the elderly.

Introduction

The world’s population is aging. The population aged 65 and above reached 398 million in 2020, about 9.3% in the total population (United Nations, 2019), and will reach 2 billion by 2050 (Clegg et al., 2013). Increased age is associated with cognitive impairment, including dementia and mild cognitive impairment (MCI). Dementia is characterized by the decline of memory, thinking, perception, language, decision-making, planning, and reasoning (Power et al., 2019). Globally, almost 50 million population are dementia, and the number will increase to 152 million by 2050 (World Health Organization, 2019). Dementia increases with age and is about 5.0% for people between 71 and 79 years old, 24.2% for people between 80 and 89 years old, and 34.7% for people aged 90 years or older (Plassman et al., 2007). Among dementia, Alzheimer’s disease (AD) is the most common type (World Health Organization, 2019). MCI is a stage between normal cognitive aging and dementia (Power et al., 2019), and it is about 10–20% in the population aged 65 years and above according to different diagnostic criteria, and it increases with age (Langa and Levine, 2014). MCI is assumed to be a precursor of dementia; MCI individuals have higher risk of dementia, and about 14.9% MCI elderly will be dementia in 2 years (Morley, 2018; Petersen et al., 2018).

Dementia could cause disability and dependency and results in a huge economic and social burden (Wimo et al., 2017). Therefore, there is a growing need to identify the mechanisms of aging-related cognitive impairment with a perspective on potential targets and explore interventions that can improve or maintain cognition and delay the progression of dementia. In the current study, we reviewed mechanisms of aging and cognitive impairment and summarized evidence of both pharmacological and non-pharmacological interventions and hoped to provide evidence for future studies.

Aging and cognitive impairment

As reported previously (Satoh et al., 2017), aging will result in the decline of cognitive function and alterations in brain structure. It leads to brain atrophy, especially in the hippocampus and prefrontal cortex (Satoh et al., 2017). Brain atrophy is related to age-related neuronal loss, reduced neurogenesis, and reduction in dendritic branching and dendritic spines. Aging also affects synapse density and synaptic function, leading a reduced synaptic transmission and plasticity (Bettio et al., 2017). Numerous factors contribute to structural and functional changes. Aging leads to intracellular accumulation of ROS, causing damage to cellular macromolecules and mitochondria (Castelli et al., 2019). Aging also induces microglia and astrocyte activation, leading to excessive neuroinflammation and consequent neuronal damage (Clarke et al., 2018; Edler et al., 2021). Amyloid-β deposition and tau aggregation have also been found in the aging brain (Zhang et al., 2021). Neurotrophins are associated with neurogenesis, neuronal survival, and synaptic plasticity (Sardar et al., 2021). Disruption of brain-derived neurotrophic factor (BDNF) and vascular endothelial-derived growth factor (VEGF) signaling in the aging brain was also associated with cognitive deficits (Bettio et al., 2017). Another factor to consider about the aging brain and impaired cognition is the decreased level of neurotransmitters, such as dopamine and serotonin (Peters, 2006). Aging contributes to cognitive decline, resulting in healthy individuals to neurodegenerative diseases, particularly AD. An increasing number of studies suggest normal aging and neurodegenerative disorders share similar functional, structural, and cellular changes. However, the structural brain changes are much more significant in neurodegenerative disorders (Yankner et al., 2008; Bettio et al., 2017).

Pharmacological interventions for cognition improvement in the aging brain

Successful drug development for improving or maintaining cognition in seniors is critically important. Although many novel targets are being explored for improving cognition in the past two decades, there are only several drugs approved to improve cognition in AD and, no drug has been approved for cognitive protection in MCI patients (Fink et al., 2018; Petersen et al., 2018). Here, we introduced the clinical evidence on the approved drugs and promising drug targets (Table 1).

Cholinesterase inhibitors

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).

Memantine

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).

Antidiabetic agents

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).

Intranasal insulin

Intranasal administration of insulin can increase insulin levels in the central nervous system (de la Monte, 2013; Erichsen et al., 2021). Previous studies demonstrated that intranasal insulin had potentially beneficial effects on cognitive functions (Reger et al., 2006, 2008a,b). 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., 2006, 2008a,b). Craft et al. (2012) reported chronic intranasal insulin therapy could preserve general cognition and improve delayed memory in MCI and AD patients. These findings indicate the potential beneficial effect of insulin on cognitive decline.

Metformin

Metformin is a first-line antihyperglycemic drug and works by increasing insulin sensitivity in peripheral tissues and suppressing hepatic gluconeogenesis (Boccardi et al., 2019). Although a meta-analysis of 6 cohort studies has shown metformin might reduce the incidence of dementia in diabetic patients (Campbell et al., 2018), the evidence of metformin usage in non-diabetic adults is still limited. In a pilot randomized controlled trial with 80 MCI adults, metformin was found to increase verbal memory. Metformin was tolerated by 92.5% of participants, and no serious adverse events occurred (Luchsinger et al., 2016). 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., 2017), which revealed the potential beneficial effect of metformin in the elderly.

Cerebrolysin

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.

Potential drugs with novel mechanisms

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).

Phosphodiesterases inhibitors

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., 2018). Almost all PDE isoforms are mostly expressed in the brain, especially in learning and memory regions (Wu et al., 2018). PDEs inhibitors showed remarkable cognitive enhancement in preclinical studies (Bruno et al., 2011; Peters et al., 2014; Zhang et al., 2018), and some PDE inhibitors have been tested in clinical trials. Most showed good safety and tolerability in phase I trial, and over 10 are in phase II/III/IV trials. Vinpocetine is a classical PDE1 inhibitor and was discovered about 40 years ago (Prickaerts et al., 2017). Though vinpocetine was found effect in improving learning and memory in preclinical study, vinpocetine didn’t show beneficial effect on cognition in AD patients (Szatmari and Whitehouse, 2003). Cilostazol is a selective PDE3 inhibitor. Cilostazol coadministration with donepezil or galantamine ameliorated cognitive decline efficiently in patients with moderate AD (Arai and Takahashi, 2009; Hishikawa et al., 2017). A cohort study recruiting 9148 participants found cilostazol treatment reduced the risk of developing dementia (Tai et al., 2017). Roflumilast is a selective PDE4 Inhibitor. Roflumilast has completed the phase II trial as a cognition enhancer in healthy adults (Van Duinen et al., 2018). PF-04447943 is a selective PDE9A inhibitor. Although PF-04447943 was safe and well-tolerated, PF-04447943 administration did not affect cognition when compared to the placebo (Schwam et al., 2014).

Muscarinic and nicotinic acetylcholine receptor agonists

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., 2020). Unfortunately, later developed highly selective M1 mAChRs agonists, such as PF-06767832, MK-7622, and PF-06764427, lead to cholinergic toxicity and behavioral convulsions (Davoren et al., 2016; Voss et al., 2018). 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-6124) and TC-1734 (AZD-3480). 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., 2019). TC-1734 is a selective α4β2 nAChR agonist (Dunbar et al., 2011). A randomized placebo-controlled trial investigated its effects on cognition. Compared to the placebo group, patients in TC-1734 (50 mg) groups showed superior performance on attention and episodic memory (Dunbar et al., 2011). In addition, a phase II trial analyzed its effect on cognitive function in MCI adults (Cummings et al., 2021). 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., 2018).

Dopamine agonist

Decreased release of dopamine and decreased expression of dopamine receptors are associated with age-related cognitive decline (Volkow et al., 2000). 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., 2012; Martorana and Koch, 2014). In a trial of 60 participants, dopaminergic agonist piribedil administration improves global cognitive function in MCI patients (Nagaraja and Jayashree, 2001). Koch et al. (2020) investigated the effect of the dopaminergic agonist rotigotine on cognitive functions in mild to moderate AD, and found rotigotine did not affect global cognition; however, it could improve cognition associated with the frontal lobe. Monoamine oxidase B (MAO-B) inhibition could increase the availability of dopamine (Koch et al., 2020). 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., 2021). Larger sample size trials are needed to evaluate the effect of dopaminergic stimulation on cognitive impairment.

Cognitive enhancing drugs in healthy adults

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).

Non-pharmacological interventions for cognition improvement in the aging brain

A growing number of studies show that non-pharmacological interventions can enhance cognition in the last decade (Gavelin et al., 2020; Sikkes et al., 2021). 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., 2021).

Cognition-oriented interventions

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.

Non-invasive brain stimulation

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.

Transcranial electrical stimulation

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., 2020). 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 (0.06 mA/cm²) but not higher current density (0.08 mA/cm²) enhanced cognition (Cai et al., 2019). 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., 2021).

Transcranial magnetic stimulation

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., 2018). 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., 2017). rTMS has been widely investigated in depression, and it has been approved by FDA for medication-resistant depression (Iriarte and George, 2018). In recent years, rTMS has been considered as a promising intervention for cognitive improvement (Iriarte and George, 2018). Two systematic reviews reported high frequency rTMS might show a moderate effect on cognition in AD and MCI patients (Cheng et al., 2018; Xie et al., 2021). 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.

Dietary and nutrition

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.

Exercise

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).

Dance intervention

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.

Multi-domain interventions

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).

Conclusion

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.

References

• 1

  AlvarezX. A.CacabelosR.SampedroC.CouceiroV.AleixandreM.VargasM.et al (2011). Combination treatment in Alzheimer’s disease: Results of a randomized, controlled trial with cerebrolysin and donepezil.Curr. Alzheimer Res.8583–591. 10.2174/156720511796391863

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 2

  AndrieuS.GuyonnetS.ColeyN.CantetC.BonnefoyM.BordesS.et al (2017). Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial.Lancet Neurol.16377–389. 10.1016/S1474-4422(17)30040-6

  • CrossRef
  • Google Scholar
  • View reference in article

• 3

  AngevarenM.AufdemkampeG.VerhaarH. J.AlemanA.VanheesL. (2008). Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment.Cochrane Database Syst. Rev.Cd005381. 10.1002/14651858.CD005381.pub3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 4

  AraiH.TakahashiT. (2009). A combination therapy of donepezil and cilostazol for patients with moderate Alzheimer disease: Pilot follow-up study.Am. J. Geriatr. Psychiatry17353–354. 10.1097/JGP.0b013e31819431ea

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 5

  Areosa SastreA.VernooijR. W.González-Colaço HarmandM.MartínezG. (2017). Effect of the treatment of Type 2 diabetes mellitus on the development of cognitive impairment and dementia.Cochrane Database Syst. Rev.6:Cd003804. 10.1002/14651858.CD003804.pub2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 6

  Bahar-FuchsA.MartyrA.GohA. M.SabatesJ.ClareL. (2019). Cognitive training for people with mild to moderate dementia.Cochrane Database Syst. Rev.3:Cd013069. 10.1002/14651858.CD013069.pub2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 7

  BattleC. E.Abdul-RahimA. H.ShenkinS. D.HewittJ.QuinnT. J. (2021). Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: A network meta-analysis.Cochrane Database Syst. Rev.2:Cd013306. 10.1002/14651858.CD013306.pub2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 8

  BattledayR. M.BremA. K. (2015). Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review.Eur. Neuropsychopharmacol.251865–1881. 10.1016/j.euroneuro.2015.07.028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 9

  BettioL. E. B.RajendranL.Gil-MohapelJ. (2017). The effects of aging in the hippocampus and cognitive decline.Neurosci. Biobehav. Rev.7966–86. 10.1016/j.neubiorev.2017.04.030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 10

  BirksJ. (2006). Cholinesterase inhibitors for Alzheimer’s disease.Cochrane Database Syst. Rev.2006:Cd005593. 10.1002/14651858.CD005593

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 11

  BirksJ. S.Grimley EvansJ. (2015). Rivastigmine for Alzheimer’s disease.Cochrane Database Syst. Rev.Cd001191. 10.1002/14651858.CD001191.pub3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 12

  BirksJ. S.HarveyR. J. (2018). Donepezil for dementia due to Alzheimer’s disease.Cochrane Database Syst. Rev.6:Cd001190. 10.1002/14651858.CD001190.pub3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 13

  BoccardiV.MuraseccoI.MecocciP. (2019). Diabetes drugs in the fight against Alzheimer’s disease.Ageing Res Rev.54:100936. 10.1016/j.arr.2019.100936

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 14

  BrunoO.FedeleE.PrickaertsJ.ParkerL. A.CanepaE.BrulloC.et al (2011). GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses.Br. J. Pharmacol.1642054–2063. 10.1111/j.1476-5381.2011.01524.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 15

  BrunoniA. R.Sampaio-JuniorB.MoffaA. H.AparícioL. V.GordonP.KleinI.et al (2019). Noninvasive brain stimulation in psychiatric disorders: A primer.Braz. J. Psychiatry4170–81. 10.1590/1516-4446-2017-0018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 16

  BuccafuscoJ. J. (2009). Emerging cognitive enhancing drugs.Expert. Opin. Emerg. Drugs14577–589. 10.1517/14728210903257796

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 17

  CaiM.GuoZ.XingG.PengH.ZhouL.ChenH.et al (2019). Transcranial direct current stimulation improves cognitive function in mild to moderate Alzheimer disease: A meta-analysis.Alzheimer Dis. Assoc. Disord.33170–178. 10.1097/WAD.0000000000000304

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 18

  CampbellJ. M.StephensonM. D.de CourtenB.ChapmanI.BellmanS. M.AromatarisE. (2018). Metformin use associated with reduced risk of dementia in patients with diabetes: A systematic review and meta-analysis.J. Alzheimers Dis.651225–1236. 10.3233/JAD-180263

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 19

  CastelliV.BenedettiE.AntonosanteA.CatanesiM.PitariG.IppolitiR.et al (2019). Neuronal cells rearrangement during aging and neurodegenerative disease: Metabolism, oxidative stress and organelles dynamic.Front. Mol. Neurosci.12:132. 10.3389/fnmol.2019.00132

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 20

  CespónJ.MiniussiC.PellicciariM. C. (2018). Interventional programmes to improve cognition during healthy and pathological ageing: Cortical modulations and evidence for brain plasticity.Ageing Res. Rev.4381–98. 10.1016/j.arr.2018.03.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 21

  ChanJ. S. Y.WuJ.DengK.YanJ. H. (2020). The effectiveness of dance interventions on cognition in patients with mild cognitive impairment: A meta-analysis of randomized controlled trials.Neurosci. Biobehav. Rev.11880–88. 10.1016/j.neubiorev.2020.07.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 22

  ChenX.MaguireB.BrodatyH.O’LearyF. (2019). Dietary patterns and cognitive health in older adults: A systematic review.J. Alzheimers Dis.67583–619. 10.3233/JAD-180468

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 23

  ChengC. P. W.WongC. S. M.LeeK. K.ChanA. P. K.YeungJ. W. F.ChanW. C. (2018). Effects of repetitive transcranial magnetic stimulation on improvement of cognition in elderly patients with cognitive impairment: A systematic review and meta-analysis.Int. J. Geriatr. Psychiatry33e1–e13. 10.1002/gps.4726

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 24

  ChuC. S.LiC. T.BrunoniA. R.YangF. C.TsengP. T.TuY. K.et al (2021). Cognitive effects and acceptability of non-invasive brain stimulation on Alzheimer’s disease and mild cognitive impairment: A component network meta-analysis.J. Neurol. Neurosurg. Psychiatry92195–203. 10.1136/jnnp-2020-323870

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 25

  ClarkeL. E.LiddelowS. A.ChakrabortyC.MünchA. E.HeimanM.BarresB. A. (2018). Normal aging induces A1-like astrocyte reactivity.Proc. Natl. Acad. Sci. U.S.A.115E1896–E1905. 10.1073/pnas.1800165115

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 26

  CleggA.YoungJ.IliffeS.RikkertM. O.RockwoodK. (2013). Frailty in elderly people.Lancet381752–762. 10.1016/S0140-6736(12)62167-9

  • CrossRef
  • Google Scholar
  • View reference in article

• 27

  Coelho-JúniorH. J.TrichopoulouA.PanzaF. (2021). Cross-sectional and longitudinal associations between adherence to Mediterranean diet with physical performance and cognitive function in older adults: A systematic review and meta-analysis.Ageing Res Rev.70:101395. 10.1016/j.arr.2021.101395

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 28

  CraftS.BakerL. D.MontineT. J.MinoshimaS.WatsonG. S.ClaxtonA.et al (2012). Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial.Arch. Neurol.6929–38. 10.1001/archneurol.2011.233

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 29

  CuiS.ChenN.YangM.GuoJ.ZhouM.ZhuC.et al (2019). Cerebrolysin for vascular dementia.Cochrane Database Syst. Rev.2019:CD008900. 10.1002/14651858.CD008900.pub3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 30

  CummingsJ. (2021). New approaches to symptomatic treatments for Alzheimer’s disease.Mol. Neurodegener.16:2. 10.1186/s13024-021-00424-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 31

  CummingsJ.LeeG.ZhongK.FonsecaJ.TaghvaK. (2021). Alzheimer’s disease drug development pipeline: 2021.Alzheimers Dement.7:e12179. 10.1002/trc2.12179

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 32

  DavorenJ. E.LeeC. W.GarnseyM.BrodneyM. A.CordesJ.DlugolenskiK.et al (2016). Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of efficacy and cholinergic side effects.J. Med. Chem.596313–6328. 10.1021/acs.jmedchem.6b00544

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 33

  de la MonteS. M. (2013). Intranasal insulin therapy for cognitive impairment and neurodegeneration: Current state of the art.Expert. Opin. Drug Deliv.101699–1709. 10.1517/17425247.2013.856877

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 34

  DunbarG. C.KuchibhatlaR. V.LeeG. (2011). A randomized double-blind study comparing 25 and 50 mg TC-1734 (AZD3480) with placebo, in older subjects with age-associated memory impairment.J. Psychopharmacol.251020–1029. 10.1177/0269881110367727

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 35

  EastwoodJ.WaltonG.Van HemertS.WilliamsC.LamportD. (2021). The effect of probiotics on cognitive function across the human lifespan: A systematic review.Neurosci. Biobehav. Rev.128311–327. 10.1016/j.neubiorev.2021.06.032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 36

  EdlerM. K.Mhatre-WintersI.RichardsonJ. R. (2021). Microglia in aging and Alzheimer’s disease: A comparative species review.Cells10:1138. 10.3390/cells10051138

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 37

  ErichsenJ. M.CalvaC. B.ReaganL. P.FadelJ. R. (2021). Intranasal insulin and orexins to treat age-related cognitive decline.Physiol. Behav.234:113370. 10.1016/j.physbeh.2021.113370

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 38

  FarahM. J. (2015). NEUROSCIENCE. The unknowns of cognitive enhancement.Science350379–380. 10.1126/science.aad5893

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 39

  FerrisS.SchneiderL.FarmerM.KayG.CrookT. (2007). A double-blind, placebo-controlled trial of memantine in age-associated memory impairment (memantine in AAMI).Int. J. Geriatr. Psychiatry22448–455. 10.1002/gps.1711

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 40

  FinkH. A.JutkowitzE.McCartenJ. R.HemmyL. S.ButlerM.DavilaH.et al (2018). Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: A systematic review.Ann. Intern. Med.16839–51. 10.7326/M17-1529

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 41

  FlanaganE.LamportD.BrennanL.BurnetP.CalabreseV.CunnaneS. C.et al (2020). Nutrition and the ageing brain: Moving towards clinical applications.Ageing Res. Rev.62101079. 10.1016/j.arr.2020.101079

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 42

  García-CasaresN.Gallego FuentesP.BarbanchoM.López-GigososR.García-RodríguezA.Gutiérrez-BedmarM. (2021). Alzheimer’s disease, mild cognitive impairment and mediterranean diet. A systematic review and dose-response meta-analysis.J. Clin. Med.10:4642. 10.3390/jcm10204642

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 43

  GatesN. J.VernooijR. W.Di NisioM.KarimS.MarchE.MartínezG.et al (2019). Computerised cognitive training for preventing dementia in people with mild cognitive impairment.Cochrane Database Syst. Rev.3:Cd012279. 10.1002/14651858.CD012279.pub2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 44

  GauthierS.ProañoJ. V.JiaJ.FroelichL.VesterJ. C.DopplerE. (2015). Cerebrolysin in mild-to-moderate Alzheimer’s disease: A meta-analysis of randomized controlled clinical trials.Dement. Geriatr. Cogn. Disord.39332–347. 10.1159/000377672

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 45

  GavelinH. M.DongC.MinkovR.Bahar-FuchsA.EllisK. A.LautenschlagerN. T.et al (2021). Combined physical and cognitive training for older adults with and without cognitive impairment: A systematic review and network meta-analysis of randomized controlled trials.Ageing Res. Rev.66:101232. 10.1016/j.arr.2020.101232

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 46

  GavelinH. M.LampitA.HallockH.SabatésJ.Bahar-FuchsA. (2020). Cognition-Oriented treatments for older adults: A systematic overview of systematic reviews.Neuropsychol. Rev.30167–193. 10.1007/s11065-020-09434-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 47

  GavrilovaS. I.AlvarezA. (2021). Cerebrolysin in the therapy of mild cognitive impairment and dementia due to Alzheimer’s disease: 30 years of clinical use.Med. Res. Rev.412775–2803. 10.1002/med.21722

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 48

  GrimaldiD.PapalambrosN. A.ZeeP. C.MalkaniR. G. (2020). Neurostimulation techniques to enhance sleep and improve cognition in aging.Neurobiol. Dis.141:104865. 10.1016/j.nbd.2020.104865

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 49

  GuekhtA. B.MoesslerH.NovakP. H.GusevE. I. (2011). Cerebrolysin in vascular dementia: Improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial.J. Stroke Cerebrovasc. Dis.20310–318. 10.1016/j.jstrokecerebrovasdis.2010.01.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 50

  Guzmán-RamosK.Moreno-CastillaP.Castro-CruzM.McGaughJ. L.Martínez-CoriaH.LaFerlaF. M.et al (2012). Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer’s disease.Learn. Mem.19453–460. 10.1101/lm.026070.112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 51

  HaamJ.YakelJ. L. (2017). Cholinergic modulation of the hippocampal region and memory function.J. Neurochem.142(Suppl. 2) 111–121. 10.1111/jnc.14052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 52

  HafdiM.Hoevenaar-BlomM. P.RichardE. (2021). Multi-domain interventions for the prevention of dementia and cognitive decline.Cochrane Database Syst. Rev.11:Cd013572. 10.1002/14651858.CD013572.pub2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 53

  HampelH.MesulamM. M.CuelloA. C.FarlowM. R.GiacobiniE.GrossbergG. T.et al (2018). The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease.Brain.1411917–1933. 10.1093/brain/awy132

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 54

  HersantH.GrossbergG. (2022). The ketogenic diet and Alzheimer’s disease.J. Nutr. Health Aging.26606–614. 10.1007/s12603-022-1807-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 55

  HewstonP.KennedyC. C.BorhanS.MeromD.SantaguidaP.IoannidisG.et al (2021). Effects of dance on cognitive function in older adults: A systematic review and meta-analysis.Age Ageing501084–1092. 10.1093/ageing/afaa270

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 56

  HishikawaN.FukuiY.SatoK.OhtaY.YamashitaT.AbeK. (2017). Comprehensive effects of galantamine and cilostazol combination therapy on patients with Alzheimer’s disease with asymptomatic lacunar infarction.Geriatr. Gerontol. Int.171384–1391. 10.1111/ggi.12870

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 57

  Hoevenaar-BlomM. P.RichardE.Moll van CharanteE. P.van WanrooijL. L.BusschersW. B.van DalenJ. W.et al (2021). Targeting vascular risk factors to reduce dementia incidence in old age: Extended follow-up of the prevention of dementia by intensive vascular care (preDIVA) randomized clinical trial.JAMA Neurol.781527–1528. 10.1001/jamaneurol.2021.3542

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 58

  HoskinJ. L.Al-HasanY.SabbaghM. N. (2019). Nicotinic acetylcholine receptor agonists for the treatment of Alzheimer’s dementia: An update.Nicotine Tob. Res.21370–376. 10.1093/ntr/nty116

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  HuM.WuX.ShuX.HuH.ChenQ.PengL.et al (2021). Effects of computerised cognitive training on cognitive impairment: A meta-analysis.J. Neurol.2681680–1688. 10.1007/s00415-019-09522-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  HuangY.MuckeL. (2012). Alzheimer mechanisms and therapeutic strategies.Cell1481204–1222. 10.1016/j.cell.2012.02.040

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  IlievaI. P.HookC. J.FarahM. J. (2015). Prescription stimulants’ effects on healthy inhibitory control, working memory, and episodic memory: A meta-analysis.J. Cogn. Neurosci.271069–1089. 10.1162/jocn_a_00776

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  IriarteI. G.GeorgeM. S. (2018). Transcranial magnetic stimulation (TMS) in the elderly.Curr. Psychiatry Rep.20:6. 10.1007/s11920-018-0866-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  JenningsA.CunnaneS. C.MinihaneA. M. (2020). Can nutrition support healthy cognitive ageing and reduce dementia risk?BMJ369:m2269. 10.1136/bmj.m2269

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  JiaR. X.LiangJ. H.XuY.WangY. Q. (2019). Effects of physical activity and exercise on the cognitive function of patients with Alzheimer disease: A meta-analysis.BMC Geriatr.19:181. 10.1186/s12877-019-1175-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  JiangD.YangX.LiM.WangY.WangY. (2015). Efficacy and safety of galantamine treatment for patients with Alzheimer’s disease: A meta-analysis of randomized controlled trials.J. Neural Transm.1221157–1166. 10.1007/s00702-014-1358-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  Kirk-SanchezN. J.McGoughE. L. (2014). Physical exercise and cognitive performance in the elderly: Current perspectives.Clin. Interv. Aging951–62. 10.2147/CIA.S39506

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  KivipeltoM.MangialascheF.NganduT. (2018). Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease.Nat. Rev. Neurol.14653–666. 10.1038/s41582-018-0070-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  KochG.MottaC.BonnìS.PellicciariM. C.PicazioS.CasulaE. P.et al (2020). Effect of Rotigotine vs placebo on cognitive functions among patients with mild to moderate Alzheimer disease: A randomized clinical trial.JAMA Netw. Open3:e2010372. 10.1001/jamanetworkopen.2020.10372

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  KoenigA. M.Mechanic-HamiltonD.XieS. X.CombsM. F.CappolaA. R.XieL.et al (2017). Effects of the insulin sensitizer metformin in Alzheimer Disease: Pilot data from a randomized placebo-controlled crossover study.Alzheimer Dis. Assoc. Disord.31107–113. 10.1097/WAD.0000000000000202

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  LangaK. M.LevineD. A. (2014). The diagnosis and management of mild cognitive impairment: A clinical review.JAMA3122551–2561. 10.1001/jama.2014.13806

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  LawC. K.LamF. M.ChungR. C.PangM. Y. (2020). Physical exercise attenuates cognitive decline and reduces behavioural problems in people with mild cognitive impairment and dementia: A systematic review.J. Physiother.669–18. 10.1016/j.jphys.2019.11.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  LiuT.LiN.HouZ.LiuL.GaoL.WangL.et al (2021). Nutrition and exercise interventions could ameliorate age-related cognitive decline: A meta-analysis of randomized controlled trials.Aging Clin. Exp. Res.331799–1809. 10.1007/s40520-020-01730-w

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  López-OrtizS.ValenzuelaP. L.SeisdedosM. M.MoralesJ. S.VegaT.Castillo-GarcíaA.et al (2021). Exercise interventions in Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials.Ageing Res. Rev.72:101479. 10.1016/j.arr.2021.101479

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  LuchsingerJ. A.PerezT.ChangH.MehtaP.SteffenerJ.PradabhanG.et al (2016). Metformin in amnestic mild cognitive impairment: Results of a pilot randomized placebo controlled clinical trial.J. Alzheimers Dis.51501–514. 10.3233/JAD-150493

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  LvT.YeM.LuoF.HuB.WangA.ChenJ.et al (2021). Probiotics treatment improves cognitive impairment in patients and animals: A systematic review and meta-analysis.Neurosci. Biobehav. Rev.120159–172. 10.1016/j.neubiorev.2020.10.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  MartinC. R.OsadchiyV.KalaniA.MayerE. A. (2018). The brain-gut-microbiome axis.Cell. Mol. Gastroenterol. Hepatol.6133–148. 10.1016/j.jcmgh.2018.04.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  MartoranaA.KochG. (2014). Is dopamine involved in Alzheimer’s disease?Front. Aging Neurosci.6:252. 10.3389/fnagi.2014.00252

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  MatsunagaS.FujishiroH.TakechiH. (2019). Efficacy and safety of cholinesterase inhibitors for mild cognitive impairment: A systematic review and meta-analysis.J. Alzheimers Dis.71513–523. 10.3233/JAD-190546

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  MatthewsD. C.RitterA.ThomasR. G.AndrewsR. D.LukicA. S.RevtaC.et al (2021). Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer’s dementia.Alzheimers Dement.7:e12106.

  • Pubmed Abstract
  • Google Scholar

• 80

  McShaneR.WestbyM. J.RobertsE.MinakaranN.SchneiderL.FarrimondL. E.et al (2019). Memantine for dementia.Cochrane Database Syst. Rev.3:Cd003154. 10.1002/14651858.CD003154.pub6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  MilićJ.ZekovićJ.StankićD.HenèićB.JanèićJ.SamardžićJ. (2021). “Chapter 33–Cognition-enhancing drugs and applications to aging,” in Assessments, Treatments and Modeling in Aging and Neurological Disease, edsMartinC. R.PreedyV. R.RajendramR. (Cambridge, MA: Academic Press), 367–378. 10.1016/B978-0-12-818000-6.00033-0

  • CrossRef
  • Google Scholar

• 82

  MorleyJ. E. (2018). An overview of cognitive impairment.Clin. Geriatr. Med.34505–513. 10.1016/j.cger.2018.06.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  NagarajaD.JayashreeS. (2001). Randomized study of the dopamine receptor agonist piribedil in the treatment of mild cognitive impairment.Am. J. Psychiatry1581517–1519. 10.1176/appi.ajp.158.9.1517

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  NganduT.LehtisaloJ.SolomonA.LevälahtiE.AhtiluotoS.AntikainenR.et al (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controlled trial.Lancet3852255–2263. 10.1016/S0140-6736(15)60461-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  OhE. S.RabinsP. V. (2019). Dementia.Ann. Intern. Med.171Itc33–Itc48. 10.7326/AITC201909030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  PetersM.BletschM.StanleyJ.WheelerD.ScottR.TullyT. (2014). The PDE4 inhibitor HT-0712 improves hippocampus-dependent memory in aged mice.Neuropsychopharmacology392938–2948. 10.1038/npp.2014.154

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  PetersR. (2006). Ageing and the brain.Postgraduate Med. J.8284–88. 10.1136/pgmj.2005.036665

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  PetersenR. C.LopezO.ArmstrongM. J.GetchiusT. S. D.GanguliM.GlossD.et al (2018). Practice guideline update summary: Mild cognitive impairment: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology.Neurology90126–135. 10.1212/WNL.0000000000004826

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  PlassmanB. L.LangaK. M.FisherG. G.HeeringaS. G.WeirD. R.OfstedalM. B.et al (2007). Prevalence of dementia in the United States: The aging, demographics, and memory study.Neuroepidemiology29125–132. 10.1159/000109998

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  PowerR.Prado-CabreroA.MulcahyR.HowardA.NolanJ. M. (2019). The role of nutrition for the aging population: Implications for cognition and Alzheimer’s disease.Annu. Rev. Food Sci. Technol.10619–639. 10.1146/annurev-food-030216-030125

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  PrickaertsJ.HeckmanP. R. A.BloklandA. (2017). Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease.Expert. Opin. Investig. Drugs261033–1048. 10.1080/13543784.2017.1364360

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  RegerM. A.WatsonG. S.FreyW. H.IIBakerL. D.CholertonB.KeelingM. L.et al (2006). Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype.Neurobiol. Aging27451–458. 10.1016/j.neurobiolaging.2005.03.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  RegerM. A.WatsonG. S.GreenP. S.BakerL. D.CholertonB.FishelM. A.et al (2008a). Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults.J. Alzheimers Dis.13323–331. 10.3233/JAD-2008-13309

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  RegerM. A.WatsonG. S.GreenP. S.WilkinsonC. W.BakerL. D.CholertonB.et al (2008b). Intranasal insulin improves cognition and modulates beta-amyloid in early AD.Neurology70440–448. 10.1212/01.WNL.0000265401.62434.36

  • CrossRef
  • Google Scholar

• 95

  Ruiz-MuelleA.López-RodríguezM. M. (2019). Dance for people with Alzheimer’s disease: A systematic review.Curr. Alzheimer Res.16919–933. 10.2174/1567205016666190725151614

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  SandersL. M. J.HortobágyiT.la Bastide-van GemertS.van der ZeeE. A.van HeuvelenM. J. G. (2019). Dose-response relationship between exercise and cognitive function in older adults with and without cognitive impairment: A systematic review and meta-analysis.PLoS One14:e0210036. 10.1371/journal.pone.0210036

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  SardarR.ZandiehZ.NamjooZ.SoleimaniM.ShiraziR.HamiJ. (2021). Laterality and sex differences in the expression of brain-derived neurotrophic factor in developing rat hippocampus.Metab. Brain Dis.36133–144. 10.1007/s11011-020-00620-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  SarkarA.HartyS.LehtoS. M.MoellerA. H.DinanT. G.DunbarR. I. M.et al (2018). The microbiome in psychology and cognitive neuroscience.Trends Cogn. Sci.22611–636. 10.1016/j.tics.2018.04.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  SatohA.ImaiS. I.GuarenteL. (2017). The brain, sirtuins, and ageing.Nat. Rev. Neurosci.18362–374. 10.1038/nrn.2017.42

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  ScarmeasN.AnastasiouC. A.YannakouliaM. (2018). Nutrition and prevention of cognitive impairment.Lancet Neurol.171006–1015. 10.1016/S1474-4422(18)30338-7

  • CrossRef
  • Google Scholar

• 101

  ScarpaM.HesseS.BradleyS. J. (2020). M1 muscarinic acetylcholine receptors: A therapeutic strategy for symptomatic and disease-modifying effects in Alzheimer’s disease?Adv. Pharmacol.88277–310. 10.1016/bs.apha.2019.12.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  SchwamE. M.NicholasT.ChewR.BillingC. B.DavidsonW.AmbroseD.et al (2014). A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer’s disease.Curr. Alzheimer Res.11413–421. 10.2174/1567205011666140505100858

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  SikkesS. A. M.TangY.JuttenR. J.WesselmanL. M. P.TurkstraL. S.BrodatyH.et al (2021). Toward a theory-based specification of non-pharmacological treatments in aging and dementia: Focused reviews and methodological recommendations.Alzheimers Dement.17255–270. 10.1002/alz.12188

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  SmithM. E.FarahM. J. (2011). Are prescription stimulants “smart pills”? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals.Psychol. Bull.137717–741. 10.1037/a0023825

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  SzatmariS. Z.WhitehouseP. J. (2003). Vinpocetine for cognitive impairment and dementia.Cochrane Database Syst. Rev.2003:CD003119. 10.1002/14651858.CD003119

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  TaiS. Y.ChienC. Y.ChangY. H.YangY. H. (2017). Cilostazol use is associated with reduced risk of dementia: A nationwide cohort study.Neurotherapeutics14784–791. 10.1007/s13311-017-0512-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  TerryA. V.Jr.BuccafuscoJ. J. (2003). The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: Recent challenges and their implications for novel drug development.J. Pharmacol. Exp. Ther.306821–827. 10.1124/jpet.102.041616

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  United Nations, (2019). World population prospects: 2019 revision. Available online at: https://data.worldbank.org/indicator/sp.pop.65up.to.zs(accessed March 22, 2022).

  • Google Scholar

• 109

  Valero-CabréA.AmengualJ. L.StengelC.Pascual-LeoneA.CoubardO. A. (2017). Transcranial magnetic stimulation in basic and clinical neuroscience: A comprehensive review of fundamental principles and novel insights.Neurosci. Biobehav. Rev.83381–404. 10.1016/j.neubiorev.2017.10.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  van BokhovenP.de WildeA.VermuntL.LeferinkP. S.HeetveldS.CummingsJ.et al (2021). The Alzheimer’s disease drug development landscape.Alzheimers Res. Ther.13:186. 10.1186/s13195-021-00927-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  Van DuinenM. A.SambethA.HeckmanP. R. A.SmitS.TsaiM.LahuG.et al (2018). Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults.Neuropharmacology13131–38. 10.1016/j.neuropharm.2017.12.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  VermaS.KumarA.TripathiT.KumarA. (2018). Muscarinic and nicotinic acetylcholine receptor agonists: Current scenario in Alzheimer’s disease therapy.J. Pharm. Pharmacol.70985–993. 10.1111/jphp.12919

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  VolkowN. D.LoganJ.FowlerJ. S.WangG. J.GurR. C.WongC.et al (2000). Association between age-related decline in brain dopamine activity and impairment in frontal and cingulate metabolism.Am. J. Psychiatry15775–80. 10.1176/ajp.157.1.75

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  VossT.LiJ.CummingsJ.FarlowM.AssaidC.FromanS.et al (2018). Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer’s disease.Alzheimers Dement.4173–181. 10.1016/j.trci.2018.03.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  WillyardC. (2021). How gut microbes could drive brain disorders.Nature59022–25. 10.1038/d41586-021-00260-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  WimoA.GuerchetM.AliG. C.WuY. T.PrinaA. M.WinbladB.et al (2017). The worldwide costs of dementia 2015 and comparisons with 2010.Alzheimers Dement.131–7. 10.1016/j.jalz.2016.07.150

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  WoodsB.AguirreE.SpectorA. E.OrrellM. (2012). Cognitive stimulation to improve cognitive functioning in people with dementia.Cochrane Database Syst. Rev.Cd005562. 10.1002/14651858.CD005562.pub2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  World Health Organization (2019). Risk reduction of cognitive decline and dementia.Geneva: World Health Organization.

  • Google Scholar

• 119

  WuY.LiZ.HuangY. Y.WuD.LuoH. B. (2018). Novel phosphodiesterase inhibitors for cognitive improvement in Alzheimer’s disease.J. Med. Chem.615467–5483. 10.1021/acs.jmedchem.7b01370

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  XieY.LiY.NieL.ZhangW.KeZ.KuY. (2021). Cognitive enhancement of repetitive transcranial magnetic stimulation in patients with mild cognitive impairment and early Alzheimer’s disease: A systematic review and meta-analysis.Front. Cell. Dev. Biol.9:734046. 10.3389/fcell.2021.734046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  YanknerB. A.LuT.LoerchP. (2008). The aging brain.Annu. Rev. Pathol.341–66. 10.1146/annurev.pathmechdis.2.010506.092044

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  ZhangK.MizumaH.ZhangX.TakahashiK.JinC.SongF.et al (2021). PET imaging of neural activity, β-amyloid, and tau in normal brain aging.Eur. J. Nucl. Med. Mol. Imaging483859–3871. 10.1007/s00259-021-05230-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  ZhangL.SeoJ. H.LiH.NamG.YangH. O. (2018). The phosphodiesterase 5 inhibitor, KJH-1002, reverses a mouse model of amnesia by activating a cGMP/cAMP response element binding protein pathway and decreasing oxidative damage.Br. J. Pharmacol.1753347–3360. 10.1111/bph.14377

  • Pubmed Abstract
  • CrossRef
  • Google Scholar