This chapter explores interventions that are aimed at improving cognition or slowing cognitive decline but that are not aimed at specific risk factors. Among the many approaches that fall into this category are cognitive stimulation through memory and other cognitive skills training, participation in the arts, technology-based cognitive stimulation, electrical stimulation, medications, and chemical stimulation such as the use of nootropic drugs or supplements. The chapter reviews studies that examine the effects on cognition of combining several interventions (e.g., physical activity, diet, cognitive stimulation) in multimodal interventions and concludes with the committee’s recommendations on next steps.
COGNITIVE STIMULATION AND TRAINING
There has been considerable scholarly and commercial interest over the past several years in the question of whether cognitive stimulation, either through such everyday activities as completing crossword puzzles, participating in a book club, playing card games, learning to play a musical instrument, and learning a new language (see Chapter 4A) or through more formal training, can assist in the maintenance or enhancement of cognitive function as people age. A second, equally important question is whether cognitive stimulation and training will transfer to real-world activities and tasks (i.e., transfer effects). For example, can a computer-based memory training program help people better remember their shopping list, medical and other appointments, and the names and faces of new acquaintances?
Or can computer-based, cognitive training improve driving performance and safety?
Fortunately, an increasing number of randomized controlled trials (RCTs) are assessing whether cognitive training, such as adaptive computer-based programs, can create improvements in trained performance and whether the benefits of such training will transfer to untrained tasks and skills. In general, these studies reveal that older adults can indeed benefit from training, albeit often at a slower rate than younger adults do (Baltes et al., 1989; Willis et al., 2006; Winocur et al., 2007). Transfer effects (benefits for untrained-for tasks) are often quite limited, as a study by Ball and colleagues (2002) illustrates. In this study, the largest RCT of cognitive training to date, 2,800 older adults were randomized among three training groups (training for memory, reasoning, and speed of processing) and a no-contact control group. Participants did improve on the trained tasks and other measures of these processes. However, no significant transfer occurred between the trained and untrained cognitive processes (e.g., those individuals receiving memory training did not improve on speed of processing and vice versa). Interestingly, the benefits of training were still observed for the reasoning and speed-of-processing groups, as compared with the control group, after 10 years. Participants in each of the three training groups also reported less difficulty with instrumental activities of daily living (IADLs), although no differences were observed for the performance-based everyday activities (Rebok et al., 2014). The IADL results should be interpreted with caution, since they might be partly attributable to expectancy differences between the training groups and the no-contact controls (Boot et al., 2013b).
Another major focus of the cognitive training literature has been on improving working memory (also see Chapter 2), on which many other cognitive processes depend (Bopp and Verhaeghen, 2005; Hale et al., 2011), which makes working memory an important target for training. It is now relatively well established that young adults show near-transfer effects with working memory. However, the transfer results for older adults have been mixed, with some studies failing to observe any transfer, even to similar memory tasks (Dahlin et al., 2008; Zinke et al., 2012), while other studies have reported transfer to similar memory tasks (Li et al., 2008; Zinke et al., 2014). A number of factors that might mediate transfer have been suggested, including age, health, general cognitive ability, baseline performance, motivation, and expectancies (Boot et al., 2011; Brehmer et al., 2011; Fairchild et al., 2013).
Another approach to strengthening cognitive skills for older adults has been the use of video games, which employ a somewhat different set of training strategies than the computer-based training. For example, Anguera and colleagues (2013) worked with video games incorporating cognitive
training tasks that have shown some promise in training and transfer in the scientific literature. These video games are believed to be more entertaining (and motivating) than most of the cognitive tasks designed by cognitive scientists, and they can adaptively increase their difficulty level as the user’s skill increases, just as “off-the-shelf” video games designed for entertainment do.
A study by Smith and colleagues (2009) used a commercially available adaptive cognitive training program focused on auditory detection, discrimination, and comprehension. The researchers compared an experimental group to an active control group that watched educational videos (1 hour daily for 40 sessions). Older adults in the active group improved, relative to the control group, on auditory measures from the Repeatable Battery for the Assessment of Neuropsychological Status as well as on other measures of attention and memory. Effect sizes were generally small to modest, and a subset of these effects was maintained over a 3-month period (Nouchi et al., 2012; Zelinski et al., 2011). Not all video game-based cognitive training programs have been as successful, with some failing to find any transfer of training effects (Ackerman et al., 2010; Owen et al., 2010) and others observing very limited transfer of training (van Muijden et al., 2012). Research on the use of video games designed for enjoyment (rather than specifically for cognitive training) has produced a mixed pattern of effects in older adults, with some showing transfer effects (Basak et al., 2008; Belchior et al., 2013) and others failing to observe them (Boot et al., 2013a).
In this report the committee does not attempt to compare one approach to cognitive training with another; rather, it considers the overall literature on this topic. The committee recognizes that future studies will better inform the research community and the general public about the effectiveness of these approaches to training, especially in whether the skills they support transfer to everyday tasks and challenges.
Ongoing debate by experts in the field about the utility of commercial cognitive training games (Cognitive Training Data, 2015; Stanford Center on Longevity, 2014) points to the need for careful evaluation of these efforts. Given the early stage of research in this field and the need to demonstrate and validate transfer effects from cognitive training products to real-life situations, consumers need information from independent evaluations of commercial cognitive training products. Questions to be examined by consumer organizations and evaluation researchers include
- Has the product demonstrated transfer of training to other laboratory tasks that measure the same cognitive construct as the training task (e.g., if some aspect of memory is being targeted in the product, is transfer demonstrated to other memory tasks)?
- Has the product demonstrated transfer of training to relevant real-world tasks?
- Has the product performance been evaluated using an active control group whose members have the same expectations of cognitive benefits as do members of the experimental group?
- How long are the trained skills retained?
- Have the purported benefits of the training product been replicated by research groups other than those selling the product?
Furthermore, the committee recommends a review of regulatory policies and guidelines (see Recommendations section) and the development of consumer product evaluation criteria for cognition-related products (see Chapter 6).
In summary, the literature on cognitive stimulation and cognitive training is promising, in that studies have shown that older adults can improve on trained abilities, albeit often at a slower pace than that of younger adults (for an exception, see Kramer et al., 1999), and that improvements on the tasks can be maintained over time (Rebok et al., 2014; Zelinski et al., 2011). Studies of the transfer of training effects to other tasks have had mixed results, with few showing transfer effects extending to tasks that are dissimilar to the training tasks (including transfer to real-world tasks and skills). As the developers of cognitive training products strive to demonstrate the benefits of these products in real-life situations, claims regarding the effectiveness of their products will require careful evaluation by consumers and in regulatory review.
Engagement in the arts has been gaining increasing interest as a potential intervention to maintain or improve a variety of aspects of health, including cognition. In general, these approaches have focused on “participatory” arts, in which the older adult is actually creating art or doing the activity rather than observing performances or discussing art. The state of the science regarding the impact of participation in writing, theater, music, dance, and visual arts has been reviewed (Noice et al., 2014). Much of the published literature reports the results of studies employing quasi-experimental and intervention designs. Moreover, many of the studies have substantial limitations in design and implementation (e.g., small sample sizes and unrepresentative samples, short follow-up, use of composite measures that may not have clinical relevance, or incomplete reporting of results). Methodological rigor might be improved by creating teams of researchers who have content and research expertise.
To date, some RCT evidence supports the use of theatrical acting,
dance, and piano playing to improve specific aspects of cognition (e.g., executive function and working memory [piano playing]; selective attention/ concentration and a composite cognition measure [dance]; recall, problem solving, and verbal fluency [acting]) (Bugos et al., 2007; Kattenstroth et al., 2013; Noice and Noice, 2009, 2013; Noice et al., 2014). However, many of the studies have inconsistent results or do not show persistent benefits. A 6-month, once-weekly dance intervention was found to improve many aspects of cognitive and physical function along with subjective well-being, without causing any improvement in physical fitness (Kattenstroth et al., 2013). Furthermore, virtually no studies directly compare different arts interventions.
In summary, despite the limitations of existing research, the results are promising. Additional studies on the influence of the arts on cognitive health are needed that have the methodological rigor that teams of researchers with expertise in the arts, cognition, and methodology can bring.
PHARMACOLOGICS, NOOTROPICS, AND SUPPLEMENTS
Pharmacologics and Nootropics
Continued controversy exists on the usefulness of medications and pharmacologics for preventing cognitive decline and for enhancing or improving cognitive function in older adults. Several medications evaluated over the past decade are thought to have cognitive-enhancing properties either directly or through disease modification. Although a few have been found to slow cognitive decline in older people with dementia, the few controlled studies in people without dementia have had mostly mixed or no results. The majority of these studies are observational, have some methodological shortcomings in design, and vary widely in how they measured cognitive function. This section highlights a few specific pharmacologics and introduces the category of nootropic medications. (As noted in Chapter 4B, there also are a number of medications that can cause cognitive decline.)
Cognitive outcomes have been examined as secondary outcomes in some studies, but few studies have focused specifically on cognitive outcomes. A 2012 prospective cohort study looked at the effects of low doses of acetylsalicylic acid on women who had high cardiovascular disease risk and were free of dementia; the women given the acetylsalicylic acid showed smaller declines in Mini-Mental State Examination (MMSE) scores than a comparison group, but the differences in scores were small. There were no differences between the groups for risk of dementia (Kern et al., 2012). A 2010 observational study of non-steroidal anti-inflammatory drug users without dementia (N = 2,300) from the Baltimore Longitudinal Study of Aging showed less decline in cognitive performance over time among users
of non-steroidal anti-inflammatory drugs when assessed on the Blessed I-M-C test (memory and attention) and Trail Making Part B. Study participants taking acetylsalicylic acid declined on several measures (Waldstein et al., 2010).
Studies of the effects of hormone therapy on cognitive function have found very small or adverse effects. A 4-year RCT of hormone treatment in postmenopausal women with cardiovascular disease did not find improvements in cognitive function compared to the use of a placebo (Grady et al., 2002). A 2008 Cochrane review of 16 double-blind RCTs showed no effects of hormone replacement therapy (either estrogen alone or in combination with progestagen) in preventing cognitive impairment (Lethaby et al., 2008). Participants in the meta-analysis were followed for an average of 4 to 5 years, and some negative effects were found after 1 year of estrogen replacement therapy and 3 and 4 years of the combined form.
Continued controversy exists regarding the hypothesis that hormone replacement therapy may confer cognitive and other benefits depending on the timing, formulation, dosage, and duration of treatment, and additional research is needed (Maki, 2013). Some have argued that cognition and verbal memory, in particular, may benefit from early hormone therapy, although this may apply only to specific combinations of hormones (Maki, 2013; Sherwin et al., 2011). Several trials are under way to attempt to address some of the questions regarding hormone therapy safety and to ascertain its impact on cognitive outcomes. The KEEPS Cognitive and Affective Study is a multicenter clinical trial investigating the benefits of hormone replacement therapies administered to perimenopausal women. This study includes women 42 to 58 years of age. The study’s primary cognitive outcome measures will include performance on tests of verbal memory and attention/executive function. Final results have not yet been published (NIH, 2014).
Nootropics are a broad range of medications, supplements, and nutriceuticals that aim to stimulate cognitive performance or facilitate learning. Most have not been evaluated in clinical trials of older people without dementia and are not focused on preventing or remediating decline. Nootropics have been classified by their mechanism of action into 19 separate categories (Froestl et al., 2014a,b,c). Some are intended to enhance cognition directly, whereas others are reputed to enhance neuronal health. Accordingly, many studies of presumed nootropics have focused on specific situations (e.g., during sleep deprivation) rather than examining the effects of long-term use on cognition. Classes of nootropics for which some evidence exists about their efficacy in people who do not have dementia include
- Racetams (e.g., piracetam): A meta-analysis of studies involving patients undergoing coronary bypass surgery suggested that racetams have short-term benefits on several dimensions of cognitive function, such as pictured object recall, delayed pictured object recall, delayed picture recognition, immediate word recall, and letter interference (Fang et al., 2014).
- Cholinesterase inhibitors (e.g., donepezil): In small, short-term (14- to 42-day) trials, donepezil improved the retention of training on complex aviation tasks and verbal memory. Studies on episodic memory show mixed results. In one study, donepezil reduced the memory and attention deficits resulting from 24 hours of sleep deprivation (Repantis et al., 2010a).
- Phenylethylamines (e.g., methylphenidate): Methylphenidate had short-term benefit on memory, especially spatial working memory, but not on attention or other dimensions of cognition (Repantis et al., 2010b).
- Eugeroics (e.g., modafinil): Modafinil improved attention for well-rested individuals, and in sleep-deprived individuals it showed beneficial effects on wakefulness, memory, and executive functions (Repantis et al., 2010b).
- Other putative nootropics (e.g., selegiline, phosphadiylserine, atomoxetine, bupropion) have not been shown to have positive benefits on cognition in humans.
The potential harms of medications and pharmacologics also need to be considered, including bleeding and effects on the central nervous and gastrointestinal systems.
The committee did not identify evidence that nootropic compounds lead to long-term improvement or the preservation of cognition. Studies that have looked for any cognition-enhancing properties of these substances have been limited by various methodological shortcomings and the risk of bias, including the lack of a consistent and standard definition for improved cognition, a paucity of RCTs, variability in the measurement of cognitive change or improvement, the short-term scale of the follow-up, and variations in drug formulations, dosages, and duration of treatment. Some of the studies cited above were designed to evaluate other questions or conditions such as cardiovascular disease or dementia.
The studies that showed minor improvements in cognitive measures did not demonstrate clinically important changes, and their impact on cognitive functioning and daily life was less clear. In conclusion, although
the situation may become clearer over time with further RCTs and larger studies, no consistent associations have yet been found. No currently available medication, either prescribed or over-the-counter, has been shown to effectively delay cognitive decline or enhance or promote cognition in healthy older adults.
Gingko biloba, an herbal extract used as a part of traditional Chinese medicine, is sold as a nutritional supplement (Birks and Grimley Evans, 2009). Numerous mechanisms have been proposed for its possible benefits, including antioxidant effects, mitochondrial protection, the promotion of hippocampal neurogenesis, decreasing blood viscosity, and the enhancing of microperfusion in the brain (Amieva et al., 2013).
In a prospective study of 3,612 cognitively healthy French men and women who were age 65 years and older at baseline and who were followed for 20 years, the scores of gingko users declined less than did those of non-supplement users on the MMSE (Amieva et al., 2013). By contrast, in a large RCT conducted in 3,069 Americans age 72 to 96 years, twice-daily supplementation with 120 mg of gingko did not affect the rate of change in scores on the MMSE compared with study participants receiving a placebo, over 6 years of follow-up (Snitz et al., 2009). A recent meta-analysis that examined the effects of gingko on cognition did not separately examine the subgroup without dementia or mild cognitive impairment (Tan et al., 2014). Given the current results of RCTs, gingko is not considered effective in preventing cognitive decline.
Coffee and tea, purportedly because of their caffeine content, are central nervous system stimulants, which increase alertness and arousal. The literature on caffeine’s effects on cognition is inconsistent but has some support in both animal and human studies. In laboratory studies of older rats, 8 weeks of coffee-supplemented diets resulted in enhanced performance on psychomotor testing and on a working memory task; the most beneficial dose was equivalent to 10 cups of coffee per day (Shukitt-Hale et al., 2013). Based on further tests in which caffeine alone did not appear to explain all of the enhanced cognitive effects, the authors concluded that other bioactive compounds in coffee may play a role (Shukitt-Hale et al., 2013).
In humans, short-term studies of caffeine have demonstrated improved perceptual speed and vigilance (Childs and de Wit, 2006). In a recent labo-
ratory study of 24 healthy older adults who were asked to perform a demanding working memory task and undergo functional magnetic resonance imaging (fMRI), the activity in the part of the brain where working memory takes places was enhanced with acute caffeine administration compared to a placebo (Haller et al., 2013).
Reviews of prospective studies have found considerable variation in their results (Arab et al., 2013; Carman et al., 2014; Vercambre et al., 2013). In a 2014 comprehensive review, 3 of 11 prospective studies and 4 of 7 cross-sectional studies found associations between caffeine intake and cognitive outcomes, with these associations being more consistent among women and for coffee consumption (Beydoun et al., 2014). Some studies found modestly reduced levels of cognitive decline associated with caffeine intake, especially coffee, while other studies showed non-significant or no associations or evidence only for coffee intake, or benefit only for women or specific exposures. For example, in the Cardiovascular Health Study (2,722 women, 2,077 men), tea and coffee intake were associated with less cognitive decline in women but not in men (Arab et al., 2011). Among 2,475 women age 65 years and older who were at high vascular risk and participated in the Women’s Antioxidant Cardiovascular Study, consumption of caffeinated coffee, but not tea, cola, or chocolate intake, was associated with a slower cognitive decline, including slower declines in global cognition, verbal memory, and category fluency (Vercambre et al., 2013).
Both animal and human short-term interventional studies support the beneficial effect of caffeine on some aspects of cognition. However, the published studies do not permit conclusions about dose or duration or about whether the effects are enduring or only short term. Data on long-term benefits are only observational and inconsistent. The dose and source (e.g., coffee versus other beverages or supplements) and whether only specific populations (e.g., women) benefit are all issues that will require further research.
TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS)
Recent studies have suggested that transcranial direct current stimulation (tDCS) may improve learning and cognitive performance by modulating the excitability of cortical brain networks (Coffmann et al., 2012; Utz et al., 2010), which are assumed to be prime brain regions that support different cognitive processes. However, much remains to be learned about the process’s safety and efficacy. tDCS uses a weak electric current (1–2 mA) administered through an electrode for 20 to 40 minutes (Brunoni et al., 2012).
Surface-anodal tDCS increases excitability in the cortex near the positive electrode through weak but coherent polarization of the membrane
potential of radially oriented axons (Reato et al., 2010). Long-term potentiation has been proposed as a possible mechanism for the longer-term and behavior-enhancing effects of tDCS (Nitsche and Paulus, 2000). At a cognitive level, tDCS may engender learning, in part, by enhancing an individual’s attention to critical stimuli and events within new tasks (Coffman et al., 2012). For example, a small study with the electrode over the right temporal parietal cortex resulted in improvement in the ability to retain object–location learning at 1 week (Floel et al., 2012). Application over the right dorsolateral prefrontal cortex was associated with increases in the proportion of performance errors that were consciously detected (Harty et al., 2014). Moreover, using a crossover sham-controlled design, tDCS administered to the left inferior frontal gyrus led to improvement in overt semantic word generation and the inducement of a more “youth-like” connectivity pattern during resting-state fMRI (Meinzer et al., 2013).
A number of theoretical and methodological issues require further study. For example, although animal studies have begun to reveal the biophysics of direct current stimulation (Bikson et al., 2004), there is still much to learn about the dependence of tDCS’s effects on N-methyl-D-aspartate glutamate receptors and on long-term potentiation and depression and also about the optimal placement and size of the stimulating electrodes and current strength, as well as about alternative stimulation techniques, such as alternating current and random noise stimulation (Fertonani et al., 2011).
In summary, tDCS shows some promise for enhancing learning and selective aspects of cognition, but further testing for both safety (especially for long-term application) and efficacy is needed before tDCS can be recommended for improving cognition and before it is known which situations are appropriate for such stimulation.
Given that some of the modifiable risk factors for cognitive decline are interrelated and that an intervention with multiple components might be more beneficial for cognitive health than one involving a single factor, multi-domain interventions are emerging as a new strategy. Of the six completed multi-domain trials described below, four have produced cognitive improvements through a combination of physical and mental activities. Two trials found that combining physical activity and cognitive training among healthy older adults was more effective at improving cognitive test scores than either intervention alone (Fabre et al., 2002; Oswald et al., 2006). Another trial examining physical activity and vitamin E supplementation found improvements in cognitive outcomes associated with physical
activity but no added benefit with vitamin E (Cetin et al., 2010). Among participants in the Mental Activity and Exercise (MAX) trial, which evaluated mental and physical activity interventions, global cognitive function improved over time, but there was no difference between intervention and control groups (Barnes et al., 2013). Two other trials, one evaluating a physical and cognitive activity intervention among older adults at risk for cognitive decline (Legault et al., 2011) and the other a diet, social, and physical activity intervention among frail older adults (de Jong et al., 2001), found no effects on cognitive outcomes. Overall, findings from multi-domain trials look promising, although conclusions cannot yet be drawn regarding any additive or synergistic effects from targeting multiple factors or about which domains yield the greatest effect.
At least seven multi-domain trials have been recently completed or are currently under way, and all have included a physical activity component. Two combined cognitive and physical activity (Gates et al., 2011; O’Dwyer et al., 2007), while another is evaluating aerobic versus resistance exercise alone or in combination with a diet intervention (Kouki et al., 2012). Another trial among frail older adults is examining the benefits of omega-3 supplementation alone or in combination with physical activity, cognitive training, and social activities (University Hospital Toulouse, 2014), and two trials involve behavioral interventions targeting mental activity and lifestyle factors related to cognitive health such as nutrition, physical and social activities, and vascular risk factors (HealthPartners Institute for Education and Research, 2009; National Institute for Health and Welfare Finland, 2014; Ngandu et al., 2014). Yet another trial is evaluating whether an intervention targeting medication compliance, blood pressure control, diet changes, and physical activity will help prevent cognitive decline among those who have had an ischemic stroke (Brainin et al., 2013; Danube University Krems, 2012).
In summary, results from multi-domain trials appear promising. Future studies should provide greater clarity regarding which combinations of factors (and which levels, duration, and treatments) yield positive benefits for general or selective aspects of cognition.
NEXT STEPS AND RECOMMENDATIONS
This and the two preceding chapters have described strengths and limitations in the evidence base for preventing and mitigating cognitive decline and promoting cognitive health. The following recommendations offer actions that individuals and their families can take, policy and regulatory efforts that are needed, and priority areas for future research.
Take Action to Support Cognitive Health
In examining the evidence base for actions by individuals and behavior changes that could be recommended, the committee found a paucity of research that focuses on preventing cognitive decline or promoting cognitive health in individuals across the life span and in those who are not diagnosed with mild cognitive impairment or neurodegenerative diseases, such as Alzheimer’s disease and other dementias. Although it is not possible to define “normal” cognitive aging because individuals vary so widely in their baseline cognition and in the way their cognitive function changes with aging, strong evidence supports several actions as having a positive impact: engaging in physical activity, monitoring medications, being aware of and preventing delirium-related cognitive changes, and reducing cardiovascular disease risk. Examples of the resources available to individuals and their families to make these changes are provided in Chapter 6. Other actions, such as getting adequate sleep, may have a positive impact on cognition, but further research is needed on non-disease-related cognitive effects and on disentangling confounding factors. At present there is a great deal of research focused on cognitive training and on games aimed at improving cognitive function. Among the issues being explored in this research are the retention of training effects and how best to transfer the gains made in gaming/training into changes in cognitive function in daily life and into related areas of cognition.
Recommendation 3: Take Actions to Reduce Risks of Cognitive Decline with Aging
Individuals of all ages and their families should take actions to maintain and sustain their cognitive health, realizing that there is wide variability in cognitive health among individuals.
Specifically, individuals should:
- Be physically active.
- Reduce and manage cardiovascular disease risk factors (including hypertension, diabetes, smoking).
- Regularly discuss and review health conditions and medications that might influence cognitive health with a health care professional.
- Take additional actions that may promote cognitive health, including
- Be socially and intellectually engaged, and engage in lifelong learning;
- Get adequate sleep and receive treatment for sleep disorders if needed;
- Take steps to avoid the risk of cognitive changes due to delirium if hospitalized; and
- Carefully evaluate products advertised to consumers to improve cognitive health, such as medications, nutritionals, and cognitive training.
Increase Research on Risk and Protective Factors and Interventions
As noted throughout the chapters, much remains to be learned about the relationship between lifestyle and risk factors and the maintenance of cognitive health throughout the adult life span. While many studies have examined dementia-based outcomes, few have examined non-dementia-related cognitive changes. For some risk factors, there are few high-quality studies examining cognitive aging, including population-based longitudinal studies and RCTs of risk factor modification. Many studies do not include sufficient numbers of older adults for valid inferences. In addition, studies are needed that consider the effects of multiple risk factors and multimorbidity, in order to better understand the cumulative contributions of different risk factors and the impact of risk factor reduction.
The assessment of cognitive function is a particular challenge (see Chapter 2). Measurement procedures (and tasks used to measure cognition) improve over time, as does the conception of various aspects of cognition. Careful measurement of baseline cognitive function, preferably at the latent variable level, is needed, as are various measurements repeated over time. Minimizing cultural, ethnic, racial, and socioeconomic biases in the measurement of risk factors and outcomes is an additional concern.
Recommendation 4: Increase Research on Risk and Protective Factors and Interventions to Promote Cognitive Health and Prevent or Reduce Cognitive Decline
The National Institutes of Health, the Centers for Disease Control and Prevention, other relevant government agencies, nonprofit organizations, and research foundations should expand research on risk and protective factors for cognitive aging and on interventions aimed at preventing or reducing cognitive decline and maintaining cognitive health.
Research efforts should:
- Develop collaborative approaches between ongoing longitudinal studies across the life span that focus on cognitive aging outcomes in order to maximize the amount and comparability of data available on risk and protective factors.
- Examine risk factors and interventions in under-studied and vulnerable populations, including people 85 years and older and those with childhood or youth trauma or developmental
- delay, mental illness, learning disabilities, or genetic intellectual disabilities and spanning ethnic/cultural and socioeconomic groups.
- Conduct single- and multicomponent clinical trials of promising interventions to promote cognitive health and prevent cognitive decline, testing for both cognitive status and functional outcomes.
- Assess cognitive outcomes in clinical trials that target the reduction of cardiovascular and other risk factors likely related to cognitive health.
- Explore older adults’ preferences and values regarding cognitive health and aging and regarding specific cognitive interventions and training modalities.
- Identify effective approaches to sustaining behavior changes that promote healthy cognition across the life span.
Policies and Regulatory Review for Cognition-Related Products
Health-related products and the advertising of those products are subject to the guidelines and regulations of the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC). FDA has the responsibility to assure the safety, effectiveness, quality, and security of drugs and medical devices and the safety and security of dietary supplements (FDA, 2014), and FTC acts to prevent “unfair, deceptive or fraudulent practices in the marketplace” (FTC, 2015). Among its responsibilities, FTC has authority to examine claims of deceptive advertising. Depending on the category of the product, federal agencies have a range of tools for regulation and review. For instance, when manufacturers wish to shift a medication from a prescription drug to an over-the-counter (OTC) medicine, FDA follows a process of evaluating safety data that will result in a product gaining or failing to gain OTC status (FDA, 2011). FDA also has the authority to review new evidence regarding the safety and side effects of medications and can consider a number of remedies in the face of newly documented risks. Depending on the severity of the risk, appropriate regulatory measures could include required changes to product labeling, such as a specific warning of a side effect. More drastic measures might include a shift from OTC status to prescription use only or an outright ban on sales of the product. As discussed in Chapter 4B, antihistamines, sedatives, and other medications that have strong anticholinergic activity, many of which are sold over the counter, have the potential to impair cognition. Although giving OTC status to popular medicines has many advantages for consumers, those advantages disappear if a medication’s risks are substantial. The risks for older consumers of the OTC products listed above indicate that additional
consumer protections may be warranted. A reexamination of product labels and OTC status could focus on the cognitive effects of these products for older adults and include a comprehensive review of currently available data regarding adverse events.
For products that claim to enhance cognitive function or to maintain current levels of function (including cognitive training products, nutriceuticals, supplements, or medications), a review of policies and regulatory guidance is needed. In 1994 the passage of the Dietary Supplement Health and Education Act1 required that dietary supplements be regulated like foods, not drugs, which denied FDA the authority to require safety and efficacy data before marketing. Consumers may believe that dietary supplements are safe because they are “natural” products; however, manufacturers of dietary supplements are not required to list risks and side effects on their packaging, and some supplements (for instance, the now-banned ephedra), have substantial risks. FDA can remove clearly dangerous products from the market, but this process is neither fast nor simple. For dietary supplements, FTC and FDA have an agreement outlining the responsibilities of each agency; FDA has primary responsibility for claims on product labeling and point-of-sale materials and FTC has the lead in responsibility for claims made in media advertising (FTC, 2001).
While the regulation of dietary supplements by FDA is difficult, the potential for FDA to regulate cognitive training products is still more uncertain. FDA would have to determine that a cognitive training product meets the definition of a medical device, and that it falls within the category of devices of sufficient risk to require oversight. Devices that may pose a major health risk if they malfunction are a focus of regulatory attention. For instance, FDA plans to oversee mobile apps that perform electrocardiography (Cortez et al., 2014). Cognitive training products seem unlikely to carry the amount of risk that currently triggers FDA scrutiny.
Current FTC and FDA guidelines and regulations allow products that are not medications to make certain general statements about the function of the product but require a substantial evidence base in order to allow specific medical claims that the product is effective in treating a specific disease (FTC, 2001). For example, either a dietary supplement or a cognitive training product would be permitted to make general claims about promoting health or cognition but would not be able to say “treats or prevents dementia.” The committee believes that in the area of cognition-related products and related product claims, current FTC and FDA guidelines and regulations need specific reconsideration from a regulatory and policy perspective to ensure that new information regarding adverse events for older
1Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 103rd Cong., 2nd sess. (October 25, 1994).
adults is appropriately reviewed and that policies reflect the current level of estimated risk. This relates to a wide range of products, including OTC medications, dietary supplements, and cognitive training products.
Recommendation 5: Ensure Appropriate Review, Policies, and Guidelines for Products That Affect Cognitive Function or Assert Claims Regarding Cognitive Health
The Food and Drug Administration and the Federal Trade Commission, in conjunction with other relevant federal agencies and consumer organizations, should determine the appropriate regulatory review, policies, and guidelines for
- over-the-counter medications (such as antihistamines, sedatives, and other medications that have strong anticholinergic activity) that may affect cognitive function, and
- interventions (such as cognitive training, nutriceuticals, supplements, or medications) that do not target a disease but may assert claims about cognitive enhancement or maintaining cognitive abilities such as memory or attention.
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