4

PRIORITIES FOR FUTURE RESEARCH

As discussed in previous chapters, none of the interventions evaluated in the Agency for Healthcare Research and Quality (AHRQ) systematic review met the criteria for being supported by high-strength evidence, based on the quality of randomized controlled trials (RCTs) and the lack of consistently positive results across independent studies (Kane et al., 2017). This underscores the need for further research on interventions that can delay or slow age-related cognitive decline (ARCD) and prevent, delay, or slow the development of mild cognitive impairment (MCI) and clinical Alzheimer’s-type dementia (CATD) (referred to throughout this report by the shorthand “prevent cognitive decline and dementia”).

In this chapter, the committee discusses priorities for future research on the three interventions highlighted in Chapter 2—cognitive training, blood pressure management, and increased physical activity—which is essential to enhance confidence in the effectiveness of these interventions and inform future communications with the public. The committee also identifies other interventions that, based on data from RCTs and observational studies, as well as a strong argument for biological plausibility, appear to be potentially promising and worth prioritizing in future research. In addition, this chapter identifies those specific interventions that the committee believes should be of lowest priority for future research because the AHRQ systematic review found no evidence of any benefit and some low-strength evidence to suggest that these interventions do not prevent cognitive decline or dementia or, in one case, some evidence of increased risk of harm.

It would be impractical for the committee to comment on every intervention that has been (or in the future could be) tested for its effect on cog-

nitive outcomes. Therefore, the discussion here is focused on those classes of interventions that appear to be promising. For ease of discussion, the identified research priorities are organized by class of intervention. However, the committee realizes that there are countless permutations of interventions that could fall within each of those domains. Recognizing that a number of intervention studies are planned or under way, far more research is needed to determine the optimal form (including dose and delivery schedule) of any specific intervention, as well as the potential for synergies when it is combined with other interventions. This chapter begins by addressing these cross-cutting considerations for intervention design, including the issue of adherence. It will be important for all future research on these interventions to attend to these design considerations in addition to the cross-cutting methodological recommendations presented in Chapter 3.

CROSS-CUTTING INTERVENTION DESIGN CONSIDERATIONS

In considering research priorities for specific intervention domains, the committee identified a number of recurring issues. Some, such as those related to optimal dose and schedule, apply to intervention research in all fields, but others are more particular to interventions focused on preventing cognitive decline and dementia. These cross-cutting issues are addressed in the sections below:

• Can combining interventions in a multimodal approach improve cognitive outcomes beyond what can be achieved through single interventions?
• For a given intervention, is there an optimal dose, delivery schedule, intervention duration, and timing that maximizes cognitive outcomes?
• How can adherence to an intervention best be promoted and measured?

As future research strategies are developed for the priority intervention domains discussed in this chapter, it will be important to incorporate each of these considerations.

Multimodal Approaches

Multimodal interventions utilize a combination of components—such as physical activity, diet, social engagement, and cognitive training—that target multiple dementia risk factors simultaneously. Although most available research on preventing cognitive decline and dementia reflects the quest for a single strong solution, multimodal approaches may be more effective than single-component interventions. ARCD, MCI, and CATD are

complex conditions with multiple, co-occurring risk factors (Etgen et al., 2011; Gottesman, 2016), and targeting several putative disease pathways simultaneously may result in synergistic effects and be more effective across a range of risk factor profiles relative to more narrowly focused interventions. This approach also may more closely resemble the real world, given that individuals are likely to engage in multiple activities that can help maintain cognitive function and reduce dementia risk (Verghese, 2016). At the same time, however, having interventions with multiple components makes it difficult to tease out the contributions of each and determine which are critical to its success.

Many multimodal RCTs conducted to date have been small and of short duration (Hars et al., 2014; Napoli et al., 2014; van de Rest et al., 2014), and thus not optimally designed for the measurement of long-term cognitive outcomes such as ARCD and CATD incidence. However, results from several larger and longer-duration multimodal studies have recently been reported. The most promising published data come from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large trial of an intervention consisting of physical activity, nutrition counseling, cognitive training, and management of vascular risk factors that was carried out in a population of adults at risk for cardiovascular disease. Although the effect of the intervention on dementia incidence was not measured, the intervention group showed significantly improved cognitive performance after 24 months compared with an attention control group (Ngandu et al., 2015). In contrast, the Prevention of Dementia by Intensive Vascular Care (PreDIVA) trial, which had a median follow-up period of 6.7 years, failed to show that a multimodal intervention targeting the reduction of cardiovascular risk factors¹ improved cognitive performance or reduced dementia incidence in older adults (aged 70 to 78) with normal cognition (Moll van Charante et al., 2016). The Multidomain Alzheimer’s Prevention Trial (MAPT), as described by Vellas and colleagues (2014), evaluated a multidomain intervention consisting of nutrition counseling, physical exercise, and cognitive stimulation, alone or in combination with omega-3 fatty acid (DHA) supplementation, in elderly people with memory complaints. Recently published results showed that after 3 years there were no significant differences in cognitive decline between intervention and placebo groups, but results from exploratory subgroup analyses suggest that the multimodal intervention may help slow cognitive decline in some high-risk groups (Andrieu et al., 2017).² Given that the effectiveness of a multimodal intervention will depend on the components it includes

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¹ In this study, the intervention group met three times per year with nurses who provided advice on healthy lifestyle and optimized treatments for hypertension, dyslipidemia, and type 2 diabetes as needed (Moll van Charante et al., 2016).

² This information has been updated since the prepublication report was released.

and baseline levels of risk factors, as well as other factors (e.g., dose, adherence, schedule), multiple independent studies testing the same combination of component elements will be necessary before strong conclusions can be drawn regarding the effectiveness of any specific multimodal intervention.

Interest in multimodal approaches is likely to grow as more studies with positive results are published. For those single-component interventions that have shown promise (e.g., cognitive training, physical activity), multimodal studies can assess whether there is an added benefit in the presence of one or more other component interventions. Ongoing and future RCTs may provide a better understanding of the optimal combinations of component elements. Data from large observational studies, such as the Framingham Heart Study, which examines temporal trends in dementia incidence and identifies key risk factors (Satizabal et al., 2016), also may be helpful for informing the development of multimodal interventions that target multiple risk factors simultaneously.

Going forward, it will be important to design trials when possible in a way that allows for the separation of effects that result from the individual components. Studies that compare cognitive outcomes for interventions both alone and in combination with others in a multimodal format may help elucidate the potential for synergistic effects (Martin et al., 2007; Napoli et al., 2014). Studies with a factorial design, such as that used in the Mental Activity and Exercise (MAX) trial (Barnes et al., 2013), may yield results that are more informative regarding the value of multimodal versus single-component interventions. For some multimodal interventions, however, it may be more difficult to isolate the components. For example, the Baltimore Experience Corps intervention trial, which trained older adults to work as volunteers in elementary schools, was intentionally designed to boost a broad array of cognitive abilities (e.g., memory, planning, organizational skills), increase physical activity, and provide opportunities for social engagement in a complex, real-world environment (Carlson et al., 2008). The pilot study, which was not included in the AHRQ systematic review because of a high risk of bias from attrition, showed that the intervention group demonstrated improved memory and executive function, while declines were observed in a waitlist control group. It is not possible, however, to separate out the effects of increased cognitive stimulation, physical activity, and social engagement for this complex intervention, highlighting the potential challenges of a multimodal approach.

Dose, Delivery Schedule, Intervention Duration, and Timing

The optimization of dose, delivery schedule, and intervention duration is a common challenge for intervention research. The evaluation of multiple conditions for each of these parameters can rapidly increase the

complexity and cost of an RCT, but until multiple permutations have been tested, it is not clear whether a negative result is indicative of an ineffective intervention or one or more of these parameters being suboptimal. For some interventions, there may be a clear biological reason for the selection of ranges for each of these parameters; for others, however, the process is one of trial and error and requires consideration of feasibility. As discussed in Chapter 3, pragmatic clinical trial designs can offer a more efficient and cost-effective means of comparing such conditions as dose and delivery schedule for interventions that have already shown some promise.

The timing of an intervention relative to the onset of pathophysiological changes (which may occur at different ages in different people) also can have a large impact on the likelihood of observing a benefit. This parameter is especially relevant for interventions targeting cognitive decline and dementia given that degeneration occurs before symptoms manifest and, as discussed in Chapter 3, some interventions may need to be initiated long before symptoms are apparent (e.g., in midlife) to prevent or delay disease.

Adherence

One final cross-cutting consideration for future intervention research studies is the challenge of promoting adherence to interventions, as lack of adherence may reduce the observed effect of an intervention on cognitive outcomes. In several studies, the strongest effect for an intervention was observed in subgroups of individuals who were adherent (Moll van Charante et al., 2016; Singh et al., 2014), highlighting the challenges associated with poor adherence that affect assessment of efficacy in the study setting. This is an important issue not only for evaluating the effectiveness of an intervention in the context of a study but also for developing strategies for communicating with the public about the value of specific interventions.

Many factors may affect adherence, including opportunities for social interaction and even environmental conditions (Dalton et al., 2016). Cognitive impairment raises additional barriers, particularly for medication adherence (Campbell et al., 2012). A number of strategies can be used to improve adherence, including providing reminders, simplifying treatment regimens, and engaging family members as appropriate (Atreja et al., 2005). A recent intervention approach—just-in-time adaptive interventions, which are being used to drive health behavior changes and focus on providing the right type and amount of support at the right time by considering an individual’s specific conditions (Nahum-Shani et al., 2016)—may have particular utility in addressing this challenge.

HIGHEST-PRIORITY RESEARCH NEEDS TO STRENGTHEN SUPPORT FOR COMMUNICATING WITH THE PUBLIC ABOUT INTERVENTIONS WITH ENCOURAGING EVIDENCE

The three classes of interventions discussed in Chapter 2—cognitive training, blood pressure management for people with hypertension, and increased physical activity—are supported by encouraging but inconclusive evidence. Before developing public health campaigns that strongly encourage the adoption of these interventions for the purpose of maintaining cognitive function, additional research is needed to further understand and gain confidence in their effectiveness. Research priorities specific to each of these intervention domains are discussed in the sections below.

Cognitive Training

A beneficial effect of cognitive training in delaying age-related cognitive decline is supported by moderate-strength evidence (Kane et al., 2017). As discussed in Chapter 2, however, the existing body of evidence is limited, and the AHRQ systematic review findings were based primarily on a single large and long-duration study—the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial.³ Because of the many uncertainties about the ACTIVE trial (e.g., which components of the intervention were important, the high attrition for 10-year follow-up results, multiple comparisons), replication by additional trials (both costly and lengthy) may not be successful. Before embarking on replication, it is important to determine how the complex ACTIVE trial of a relatively short-duration intervention had such an apparently long-lasting effect in some domains but not others. This will be challenging to accomplish after the fact, but may be feasible using newer statistical methods developed for clinical trials with attrition and mediation effects provided adequate data are available. Moreover, given the data from observational studies suggesting that education (Beydoun et al., 2014) and less structured activities such as playing games, engaging in craft activities, and computer use (Krell-Roesch et al., 2017) also may prevent cognitive decline and dementia, comparative effectiveness studies of different types of cognitive training exercises, including those used in the ACTIVE trial and other cognitively stimulating activities, are needed. Recognizing that the robust kinds of long-term studies required to address current knowledge gaps are difficult to carry out, the committee

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³ This trial is described in more detail in Chapter 2, but briefly, participants were divided into reasoning, memory, and speed-of-processing groups and trained using different exercises over 5 to 6 weeks, with booster sessions similar to the initial training being administered 11 months after the initial training and again after 3 years. Participants were followed for 10 years (Jobe et al., 2001).

identified the following specific research questions that, if answered, would strengthen the evidence base for cognitive training interventions and inform the design of future trials. Answering these questions will require multidisciplinary research integrating social and behavioral science, psychology, and education.

• Which types of cognitive training activities are likely to have the greatest impact on ARCD? Do structured cognitive training interventions such as those used in the ACTIVE trial improve cognitive performance compared with other cognitively stimulating activities (e.g., reading, playing cards)?
• Which specific intervention elements, or combination of elements, used in the ACTIVE trial are responsible for the observed positive and long-term impacts on cognitive performance? For example, is it important to instruct participants in the relevance of training exercises to instrumental activities of daily living? Did the environment in which the training took place (e.g., at home alone or in a more social group setting) have an impact on the outcomes?
• Can cognitive training prevent, delay, or slow MCI and CATD in addition to delaying ARCD?
• What is the role of social engagement as part of a cognitive training intervention? Does a social aspect make cognitive training interventions more enjoyable and thereby have an effect on adherence?
• Are there any adverse effects of computer-based cognitive training applications similar to those that have been well documented in the computer gaming literature? For example, are the risks of addiction similar or reduced in an older-adult population?

Blood Pressure Management

As described in Chapter 2, the committee emphasizes that further research on the effectiveness of blood pressure management in preventing cognitive decline and dementia is a priority. A definitive answer may never be obtained through RCTs since a placebo-controlled trial may not be considered ethical in a hypertensive population, given the known cardiovascular benefits of blood pressure management. In addition, the large secular trend toward reduced dementia incidence and cardiovascular risk factors complicates efforts to study this question. Recent and ongoing RCTs, such as the Heart Outcomes Prevention Evaluation-3 (HOPE-3) (American College of Cardiology, 2016; Lonn et al., 2016), have included only relatively low-risk groups, making it challenging to power the trials adequately to identify a treatment effect. Moreover, blood pressure targets optimal for cardiovascular disease outcomes (e.g., prevention of stroke and/or heart

attack) likely will take precedence in such studies, and these targets may not be best for preventing cognitive decline and dementia (even vascular dementia). Ultimately, then, treatment recommendations may have to be based on data other than rigorous evidence derived from RCTs.

Despite these challenges, further research—and analyses of the results of studies already completed and under way—could, by improving understanding of populations most likely to benefit from treatment and guiding optimal blood pressure targets, help tailor clinical guidance and communications with the public. The question of an optimal blood pressure target for cognitive outcomes, for example, may be informed by the ongoing Systolic Blood Pressure Intervention Trial: Memory and Cognition in Decreased Hypertension (SPRINT-MIND) substudy of the Systolic Blood Pressure Intervention Trial (SPRINT), which is designed to examine the cognitive effects of more intensive antihypertensive therapy than is currently recommended for cardiovascular disease outcomes (The SPRINT Research Group, 2015). Given the documented problems with undertreatment for hypertension (Bromfield et al., 2014; Navar-Boggan et al., 2014), it will be particularly important to address adherence issues. Going forward, priority research questions include the following:

• Which populations would benefit most from blood pressure management? Are there some who might be harmed by treatment for hypertension?
• What is the optimal blood pressure management approach at different ages (e.g., midlife, late life, very late life) given the evidence on age-related heterogeneity in treatment effects?
• Is there an optimal treatment level (blood pressure target) for cognitive outcomes, and should targets differ among clinical subgroups?
• What is the comparative effectiveness of different classes of antihypertensive treatments (e.g., angiotensin II receptor blockers [ARBs] versus other treatments)?
• Does a focus on blood pressure in isolation from other vascular risk factors limit the impact on cognitive outcomes?

Increased Physical Activity

As described in Chapter 2, the data on the effects of increased physical activity on cognitive performance are promising. Most studies published to date have been of short duration, so one pressing research priority is to determine whether physical activity has long-term cognitive benefits in addition to the short-term benefits observed in some past RCTs. Moreover, it is unclear from existing studies whether there is an optimal form of physical activity (e.g., aerobic activity, resistance training, or both in combination)

for reducing the risk of cognitive decline and dementia, and whether some populations are more likely to benefit. The AHRQ systematic review found some indication that physical activity may reduce the rate of cognitive decline in individuals with MCI, but the data were not conclusive. The ongoing Exercise in Adults with Mild Memory Problems (EXERT) trial may further elucidate any benefit of aerobic activity in this population. Additional research addressing the following key questions would help strengthen and tailor communications with the public on the effects of increased physical activity on preventing cognitive decline and dementia:

• Which physical activity regimens are most promising for providing cognitive benefits?
• How does the beneficial effect of physical activity vary among subpopulations (e.g., adults with MCI or such comorbidities as diabetes)? Are there some groups for whom physical activity is ineffective, or even harmful, with respect to cognitive function?
• Are the cognitive benefits of physical activity sustained if the intervention is discontinued?

OTHER PRIORITY RESEARCH AREAS

There are a number of interventions discussed in the AHRQ systematic review for which the current evidence base from RCTs is insufficient to draw any conclusions regarding their impact on ARCD and the incidence of MCI and CATD. However, based on additional data from observational studies, knowledge of dementia risk factors, and/or a strong argument for biological plausibility, the committee identified the following intervention domains as priorities for future research:

• new antidementia treatments that can delay onset or slow disease progression
• diabetes treatment
• depression treatment
• dietary interventions
• lipid-lowering treatment
• sleep quality interventions
• social engagement interventions
• vitamin B₁₂ plus folic acid supplementation

For each of these intervention domains, the sections below summarize the findings from the AHRQ systematic review, other relevant evidence suggesting that these interventions might be promising, and potential areas for future research. A summary of the evidence for other interventions not

identified by the committee as research priorities can be found in the AHRQ systematic review (see Appendix A).

The Search for New Antidementia Treatments to Delay Onset or Slow Disease Progression

Given the expected rise in dementia prevalence in some regions of the world and as life expectancy continues to increase (discussed in Chapter 1), there is a critical need for pharmacological treatments that, though not preventing disease, can delay onset of dementia or slow progression of cognitive impairment in those with ARCD or MCI. Although such treatments are not prevention interventions in the strict sense, they can be thought of as secondary or tertiary prevention. In the past decade, the emphasis of drug development for Alzheimer’s disease has shifted from treatments that address symptoms (e.g., acetylcholinesterase inhibitors) to a search for such disease-modifying drugs, which currently is a very active area of research. However, no disease-modifying treatments have yet shown a significant drug–placebo difference in phase III studies (Siemers et al., 2016). A recent analysis of clinical trials registered on ClinicalTrials.gov found that of 24 agents being studied in phase III trials, 17 were being tested for disease-modifying effects and 7 for symptomatic effects, and among 45 agents in phase II trials, 30 were disease-modifying and 15 were symptomatic (Cummings et al., 2016a). The drugs currently being evaluated for disease modification across all phases of clinical trials target predominantly amyloid pathology. While the amyloid cascade hypothesis remains the dominant conceptual model of Alzheimer’s disease pathogenesis (Hardy and Higgins, 1992), the lack of success of antiamyloid drugs has led many investigators in the field to question whether targeting other aspects of Alzheimer’s disease pathophysiology might lead to additional mechanistically informed and more effective treatments (Cummings et al., 2016b; Hardy and De Strooper, 2017).

Future Research Questions and Directions

Antidementia treatments evaluated in studies included in the AHRQ systematic review were limited to acetylcholinesterase inhibitors, which were assessed for effects on cognitive performance in people with subjective complaints of cognitive loss or diagnosed MCI, and on progression from MCI to CATD. This class of antidementia treatments is discussed later in this chapter along with other interventions with some evidence suggesting no benefit. Future drug development aimed at delaying onset or slowing disease progression will be aided by a deeper understanding of the biological basis of Alzheimer’s disease, including the multiple mechanistic

pathways that interact to give rise to the disease (Schadt et al., 2014). Ongoing efforts to identify biomarkers that can inform the development of disease-modifying therapies and identify high-risk populations that may be targeted with such treatments, along with increasingly sophisticated clinical trial methodologies that can enhance the trials’ sensitivity and power (discussed further in Chapter 3), will help accelerate drug development. Such advances in knowledge and tools may help address the following priority research questions for antidementia treatments:

• Are there nonamyloid metabolic cascades that, if disrupted by a pharmacological agent, would halt, slow, or reverse disease progression in individuals with ARCD or MCI?
• At what stage in the process of neurobiological changes leading to cognitive decline and dementia do antidementia treatments need to be administered to optimize cognitive outcomes?

Diabetes Treatment

Diabetes is associated with an increased risk of dementia (Cheng et al., 2012; Ott et al., 1999; Rawlings et al., 2014). Moreover, high insulin levels, an important antecedent and companion of type 2 diabetes, may increase amyloid accumulation in the brain and thereby increase the risk of Alzheimer’s disease (Craft and Watson, 2004). The evidence linking diabetes with ARCD, MCI, and CATD suggests that diabetes prevention in the general population and among those at risk (e.g., individuals with prediabetes), as well as good diabetes treatment in those who have been diagnosed (i.e., controlling glycemia, lipids, and blood pressure), may have a role in preventing cognitive decline and dementia (Luchsinger, 2010). According to a 2011 study, nearly 175,000 cases of Alzheimer’s disease in the United States were attributable to diabetes, and a 25 percent reduction in diabetes prevalence could potentially have prevented 40,000 of these cases (Barnes and Yaffe, 2011). The prevalence of diabetes (and obesity), however, is increasing, threatening to reverse the apparent decline in dementia rates in some high-income countries (Larson et al., 2013).

Diabetes prevention and treatment include both nonpharmacologic and pharmacologic approaches. The former approaches use lifestyle changes (e.g., increased physical activity and reduced caloric intake) to induce weight loss. Medications used in diabetes treatment include those that increase insulin secretion or raise insulin levels (e.g., through treatment with insulin itself), as well as medications with insulin-sensitizing effects, such as metformin, pioglitazone, and rosiglitazone.

AHRQ Systematic Review Findings and Discussion

As summarized in Box 4-1, the AHRQ systematic review found little evidence from intervention studies to suggest that diabetes treatment in adults with MCI or normal cognition can prevent cognitive decline and dementia. Two RCTs evaluated the effectiveness of different insulin-sensitizing medications—pioglitazone treatment in obese older adults without diabetes (Hildreth et al., 2015) and metformin treatment in overweight nondiabetic and diet-controlled diabetic adults (Luchsinger et al., 2016)—versus placebo in a study population with MCI. Neither study found significant between-group differences in global measures of cognition or for the majority of domain-specific tests; however, these studies may have been too small and of inadequate duration to have observed an effect of the interventions. Two substantially larger RCTs—the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial (N = 12,537) and the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial (N = 2,977)—compared the effects of intensive and standard glycemic control methods on cognitive outcomes in diabetic adults presumed to have normal cognition (Cukierman-Yaffe et al., 2014; Launer et al., 2011; Seaquist et al., 2013). Both were substudies of trials designed with primary cardiovascular disease outcomes. The ORIGIN study found no difference in the risk of probable incident cognitive impairment after 6 years. Neither study found any difference in cognitive performance between treatment arms. However, less decline in brain volumes in individuals with intensive glycemic control was observed in the ACCORD study (Launer et al., 2011).

For the ORIGIN trial, there was little difference in high glycated hemoglobin A1c (HbA1c) levels—a measure of glycemic control—between intensive and standard glycemic control groups (Gerstein et al., 2012), potentially explaining the lack of observed differences in cognitive outcomes between the two study arms. This was not the case for the ACCORD trial, which was designed to test whether very tight glycemic control (glycated hemoglobin <6 percent) versus usual care improved cardiovascular outcomes among persons with diabetes (Gerstein et al., 2008). In that trial, the intervention group demonstrated significantly improved glycemic control but with no meaningful improvement in cognitive outcomes, although a reduced level of brain atrophy was observed at 40 months (Launer et al., 2011). Of note, however, the intensive glycemic control arm was stopped prematurely because of increased mortality, which to date has not been explained. It is possible that what caused this increased mortality in the intensive glycemic control arm could also have had a detrimental effect on cognition, although this possibility is speculative. Since the level of control targeted in the ACCORD trial is not the standard of care, it remains unknown whether glycemic control following the current guidelines of the American Diabetes Association (glycated hemoglobin less than 7 percent, or less than 8 percent in frail persons) (ADA, 2016) results in better cognitive outcomes. The results of one RCT of diabetes control using telemedicine versus usual care, which followed the guidelines of the American Diabetes Association for glycemic control, suggest that improved glycemic control leads to less decline in global cognition compared with usual care (Luchsinger et al., 2011). However, the AHRQ systematic review considered this study to be at high risk of bias (attrition was not clearly reported, and participants were not blinded), so it was excluded from the review.

Another important limitation of RCT data on diabetes interventions is the so-called legacy effect (Chalmers and Cooper, 2008), referring to the observation that some of the cardiovascular benefits of diabetes-related interventions take many years, if not decades, to become apparent after the intervention has ended. This observation may be true for cognitive outcomes as well, indicating that follow-up periods much longer than those in previous studies may be needed to observe a cognitive benefit (see the discussion of this issue in Chapter 3), and further highlighting the value of longitudinal observational studies.

Supplemental Information and Considerations

Although results of RCTs of diabetes treatment for preventing cognitive decline and dementia have not been encouraging, other sources of evidence indicate that further study of such interventions is warranted. A meta-analysis by Cheng and colleagues (2012) estimates that the risk of

incident Alzheimer’s disease increases by almost 50 percent in individuals diagnosed with diabetes. Furthermore, peripheral high insulin levels caused by insulin resistance are common in people with obesity, those with prediabetes, and those with type 2 diabetes. Peripheral high insulin levels may lead to increased accumulation of amyloid in the brain, one of the main pathologies of Alzheimer’s disease (Craft and Watson, 2004). Thus, it is biologically plausible that a decrease in insulin levels through pharmacologic (insulin-sensitizing drugs) or nonpharmacologic (diet and exercise leading to weight loss) means could prevent cognitive decline and dementia (Luchsinger, 2010).

Weight loss through reduced caloric intake and increased physical activity is recommended to treat overweight and obese individuals with type 2 diabetes (ADA, 2017). Although lifestyle interventions targeting weight loss in adults diagnosed with or at risk for type 2 diabetes have not resulted overall in improved cognitive outcomes (Espeland et al., 2014; Luchsinger et al., 2015; Rapp et al., 2017), one study provides some evidence that a long-term weight loss intervention may benefit cognition among individuals who are overweight, but not obese. The large Action for Health in Diabetes (Look AHEAD) RCT compared 10 years of a lifestyle intervention that resulted in weight loss with a control condition of diabetes support and education. In overweight adults (i.e., those with a body mass index of 25 to 30 kg/m²), random assignment to the intervention was associated with better cognitive function and a trend toward lower rates of MCI and CATD, but no benefits were seen among heavier individuals (Espeland et al., 2014, 2017a; Rapp et al., 2017). In addition, the lifestyle intervention was associated with better markers of brain atrophy and cerebrovascular disease. The Look AHEAD trial did not assess cognitive function prior to delivery of the intervention. For this reason, the study did not meet inclusion criteria for the AHRQ systematic review, and further study and replication are needed.

Future Research Questions and Directions

Given that diabetes is consistently identified as a risk factor for MCI and CATD, considerable interest remains in evaluating diabetes treatment as a potential intervention for the prevention of cognitive decline and dementia. Priority areas for research include the identification of optimal treatment targets (given data showing that intensive treatment is not effective), the modifying effects of other risk factors (e.g., obesity), and the relative effectiveness of different diabetes medications. Some studies now under way may help address some of these questions. Low-dose pioglitazone, a medication with more powerful insulin-sensitizing and lowering effects relative to metformin, is being tested to delay onset of MCI due to Alzheimer’s disease among nearly 3,500 cognitively normal, elderly individuals (Budur

et al., 2015). The Glycemic Reduction Approaches in Diabetes (GRADE) study (Nathan et al., 2013) is comparing insulin-sensitizing and other treatments for early diabetes, and is assessing cognition longitudinally. The committee identified the following specific areas in which additional research may lead to a better understanding of the impact of diabetes treatment on cognitive outcomes:

• Is there an optimal treatment target level? Does optimal glycemic control as currently recommended by the American Diabetes Association prevent cognitive decline among people with diabetes?
• Does a comprehensive approach to diabetes management that includes multiple treatment modalities (e.g., exercise, control of blood pressure) have a greater impact on cognitive outcomes than approaches relying on a single strategy?
• How do obesity-related factors modify the effects of diabetes interventions on cognitive outcomes?
• What is the comparative effectiveness of insulin-sensitizing versus non-insulin-sensitizing diabetes treatments?
• Can cognitive benefits of diabetes treatment be detected by starting interventions earlier in the life course and following participants for longer periods?

Depression Treatment

A number of studies and reviews have linked depression to cognitive decline (Butters et al., 2004; Goveas et al., 2014) and dementia (Byers and Yaffe, 2011; Diniz et al., 2013; Ownby et al., 2006). Although the association between late-life depression and cognitive decline and dementia may be attributed, in part, to reverse causality (that cognitive decline leads to depression, rather than the reverse) and the long prodromal stage of dementia, reverse causality does not provide a good explanation for the twofold increase in risk of cognitive impairment and dementia associated with depression in midlife (Byers and Yaffe, 2011). Barnes and Yaffe (2011) estimate that as many as 15 percent of Alzheimer’s disease cases in the United States and more than 10 percent of cases worldwide may be attributable to depression. Depression treatments include both pharmacologic treatments and nonpharmacologic approaches employing psychotherapy.

The mechanistic pathways mediating the effects of depression on cognitive decline and dementia are not well understood, but plausibly relate to the links among depression, chronic inflammation, and cerebrovascular disease. Diniz and colleagues (2013) note that the risk of vascular dementia associated with depression is higher relative to the risk of Alzheimer’s disease. Depression also is associated with elevated levels of the stress-related

hormone cortisol, which is linked to atrophy of the hippocampus, a region of the brain with a critical role in learning and memory (Lee et al., 2002).

AHRQ Systematic Review Findings and Discussion

As indicated in Box 4-2, the AHRQ systematic review identified no RCTs for depression treatment meeting the inclusion criteria. Similar to some other intervention domains (e.g., blood pressure management, diabetes treatment), RCTs for depression treatment are challenging to design since it may not be appropriate to randomize study participants with depression to a placebo control group, given the known benefits of treatment. Although active treatment comparisons and add-on studies can be designed, such studies are still logistically challenging because of the requirement for a large study population and long follow-up period to detect changes in MCI and CATD incidence. Moreover, there is significant heterogeneity in responsiveness to treatment, and in contrast to antihypertensive and diabetes treatments, the effectiveness of which can be measured through blood pressure and glycated hemoglobin, respectively, there is no clear marker for easily determining whether a patient is responding to depression treatment.

Supplemental Information and Considerations

The association between depression and cognitive decline and dementia suggests that depression treatment has the potential to prevent these conditions. The limited data from short-term RCTs and observational studies, however, have been inconclusive, and deleterious effects of treatment have been observed. Although one RCT found a significant improvement in cognitive function when elderly patients (aged 65 to 90) with recurrent depression were treated with a serotonin-norepinephrine reuptake inhibitor (Raskin et al., 2007), another RCT showed that treatment of depressed patients aged 75 and older with a selective serotonin reuptake inhibitor (SSRI) resulted in a decline in cognitive function for treatment

nonresponders relative to a placebo group (Culang et al., 2009). Both RCTs were too short (8 weeks), however, to permit conclusions regarding long-term effects of treatment. A large and long-duration prospective cohort study examining the effect of antidepressant use (SSRIs and tricyclic antidepressants) on the incidence of MCI and dementia in women aged 65 to 79 found a 70 percent increased risk of MCI for those being treated with antidepressants relative to nonusers, even after controlling for severity of depressive symptoms (Goveas et al., 2012). However, the study authors were unable to disentangle the relative contributions of depression and antidepressant use to the cognitive outcomes. These findings highlight the need for additional research, including trials on the effect of antidepressants on cognitive outcomes in individuals both with and without depression.

Future Research Questions and Directions

The link between depression and cognitive decline and dementia strengthens the argument for an aggressive, proactive, and ongoing approach to depression treatment. However, much remains unknown regarding the links between depression and cognitive decline and dementia and the impact of depression treatment on dementia risk. The following fundamental research questions are priorities for future studies:

• What are the biological mechanisms by which depression might lead to dementia?
• Does early identification and treatment of depression lower the risk of dementia?

Dietary Interventions⁴

Epidemiologic evidence links diet—primarily Mediterranean-style diets⁵—to prevention of Alzheimer’s disease, and is supported by underlying biological mechanisms in the etiology of the disease (Singh et al., 2014; van de Rest et al., 2015). Further evidence suggests that diets targeting weight loss may address other dementia risk factors, such as diabetes and obesity. Despite evidence from observational studies linking diet to brain health, however, most RCTs examining effects of diet on the risk of Alzheimer’s disease have been negative. To date, the majority of such RCTs have focused

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⁴ Consistent with the AHRQ systematic review, vitamins were considered separately from dietary interventions for the purposes of this report, and certain specific vitamins are addressed elsewhere in this chapter.

⁵ The Mediterranean diet emphasizes consumption of fruits and vegetables, cereals, legumes, fish, and unsaturated fats (i.e., olive oil) and lower levels of saturated fats such as those found in meats and dairy products.

on either individual foods or high-dose nutrient supplements. Few have examined comprehensive diets, such as the Mediterranean diet, which is high in antioxidants and thought to protect against the primary biological mechanisms underlying Alzheimer’s disease—oxidative stress and inflammation (Fitó et al., 2007; Mitjavila et al., 2013; Zamora-Ros et al., 2013).

AHRQ Systematic Review Findings and Discussion

Although the AHRQ systematic review initially identified six RCTs of the effect of diet-based interventions on cognitive function, all but two studies were excluded from the analysis because of a high risk of bias, and evidence from the two remaining trials was insufficient to permit any conclusions regarding efficacy (see Box 4-3). In adults with normal cognition, one small RCT (N = 65) showed that twice-daily consumption of a protein supplement drink had no effect on cognitive function in frail elderly adults after 24 weeks (van der Zwaluw et al., 2014b). Another small RCT (N = 107) in obese adults showed improvement in Brief Cognitive Test performance after 1 year for an energy-deficient diet intervention group compared with controls (Napoli et al., 2014). No eligible studies examined the effect of diet-based interventions on cognition in adults with MCI.

Supplemental Information and Considerations

Although RCTs of comprehensive diets (such as the Mediterranean diet) were excluded from the AHRQ systematic review because of a high risk of bias, promising data from observational studies indicate that additional research on such diets is needed. A number of observational studies have suggested the possibility that some types of diets can prevent cognitive decline and dementia (IOM, 2015; van de Rest et al., 2015). Specific diets found in these studies to be associated with improved cognitive function or reduced

incidence of MCI or CATD include the Mediterranean diet (Scarmeas et al., 2009), the Dietary Approaches to Stop Hypertension (DASH) diet (Tangney, 2014; Tangney et al., 2014), and the Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) diet—a hybrid of the Mediterranean and DASH diets designed to focus on foods that are specific to brain health (Morris et al., 2015a,b).

Observational data on the Mediterranean diet are bolstered by a post hoc analysis of cognitive outcomes from the PREDIMED (Prevención con Dieta Mediterránea) RCT, which evaluated the effect of the Mediterranean diet in a population at high vascular risk and found statistically significant improvements in cognition compared with a control group on a low-fat diet (Martinez-Lapiscina et al., 2013; Valls-Pedret et al., 2015). However, these studies were considered to be at high risk of bias because of high levels of attrition, and therefore were not considered in the AHRQ systematic review. Also, in the study by Martinez-Lapiscina and colleagues (2013), cognitive function was not assessed at baseline since the primary aim of the RCT was to evaluate the effect of the diet on incident cardiovascular disease.

Future Research Questions and Directions

As noted above, the majority of past dietary interventions have been focused on individual nutrient supplements (e.g., DHA) or single foods (e.g., fish, olive oil), not comprehensive diets that capture dietary components working in synergy. Intervention studies of such comprehensive diets (alone or in combination with other lifestyle interventions) are currently under way (Blumenthal et al., 2013) and, unlike studies evaluating single foods or nutrient supplements, will enable evaluation of entire dietary patterns and how they may impact neurodegeneration leading to changes in cognition. One recently funded trial of the MIND diet includes another methodological improvement over past diet trials in that only those with suboptimal diets for the foods included in the MIND diet will be randomized. Not only will this approach allow for a better contrast between the intervention and control groups, but it has the potential to help researchers define a target population for prevention and treatment studies. These and future studies may help address the following priority research questions regarding dietary interventions:

• Which foods are critical to brain health and should be included in diet-based interventions?
• Which populations are likely to benefit most from dietary interventions targeting prevention of cognitive decline and dementia?
• Do dietary interventions have a larger effect on late-life ARCD, MCI, and CATD if initiated in midlife?

Lipid-Lowering Treatment

Hyperlipidemia—particularly hypercholesterolemia—is associated with cognitive decline (Etgen et al., 2011; IOM, 2015). Moreover, cholesterol has been linked to the generation and deposition of beta-amyloid plaques (Pappolla et al., 2003; Puglielli et al., 2001), one of the hallmarks of Alzheimer’s disease. Intervention studies of lipid-lowering treatments have been pursued based on the known effects of these drugs on vascular health, including stroke risk, which over time may also prevent cognitive decline and dementia. Most research on cognitive effects of lipid-lowering treatments has been focused on cholesterol-lowering statins (e.g., simvastatin, atorvastatin, lovastatin); far fewer studies have evaluated the efficacy of other lipid-lowering treatments, such as ezetimibe, which blocks cholesterol absorption.

AHRQ Systematic Review Findings and Discussion

The AHRQ systematic review found no evidence of cognitive benefit for lipid-lowering treatments in adults with normal cognition (see Box 4-4 for a summary of the AHRQ findings). Four RCTs, including the large (N = 20,536) and long-duration (5 years) Heart Protection Study (Heart Protection Study Collaborative Group, 2002), evaluated statins against

placebo. Only the Heart Protection Study measured dementia incidence, and no between-group differences in dementia incidence or Brief Cognitive Test performance were identified for adults aged 40 to 80 with coronary disease, other occlusive arterial disease, or diabetes. Of the three other RCTs in adults with very high cholesterol levels, one found no between-group difference in cognitive performance (Santanello et al., 1997), and the other two found statistically significant increases in cognitive performance for the placebo group (Muldoon et al., 2000, 2004); these may have resulted from practice effects (Kane et al., 2017). One very small study (N = 34) showed that statins combined with ezetimibe resulted in slightly improved cognitive performance at 1 year as compared with placebo (Tendolkar et al., 2012), but these between-group differences were small and may not be clinically meaningful (Kane et al., 2017). A combination therapy consisting of statins and fenofibrate (another lipid-lowering drug) did not improve cognitive performance beyond statins alone in the ACCORD-MIND trial (Williamson et al., 2014). No studies included in the AHRQ systematic review evaluated the efficacy of statins in adults with MCI, so conclusions cannot be drawn regarding the ability of these drugs to prevent or delay dementia in this subpopulation.

Although results from the limited number of RCTs included in the AHRQ systematic review are not very promising, it should be noted that follow-up periods were short (6 months) for all but the Heart Protection Study and may not have been sufficient to show beneficial cognitive effects of statins and other lipid-lowering treatments. The longer Heart Protection Study was originally designed to measure cardiovascular outcomes (cognitive outcomes were added on) and did not include a baseline measure of cognition.

Supplemental Information and Considerations

In contrast to the RCT data reviewed in the AHRQ report, many observational studies suggest that statins could have the potential to prevent cognitive decline and dementia (Haag et al., 2009; Steenland et al., 2013; Wolozin et al., 2000; Zissimopoulos et al., 2016). The Rotterdam Study found that the risk of developing CATD was reduced by nearly 50 percent in study participants taking statins (Haag et al., 2009). As is the case with hypertension (discussed in Chapter 2), hyperlipidemia in midlife may be an important risk factor for cognitive decline (Kivipelto et al., 2001; van Vliet, 2012; Whitmer et al., 2005), suggesting that RCTs with longer follow-up periods are needed to evaluate the effects of lipid-lowering treatment on cognitive outcomes. Some inconsistent evidence suggests possible differential effects in older (more than 80 years of age) individuals (Harrison et al., 2015).

In addition to lowering lipids, statins may work via amyloidogenic pathways involved in the development of CATD (Barnard et al., 2014). This may, in part, explain why Haag and colleagues (2009) observed reduced CATD risk associated with the use of statins, but not other cholesterol-lowering drugs. The lipid transport molecule Apolipoprotein E4 increases the risk of CATD via amyloidogenic pathways, and basic research evidence supports this notion (Puglielli et al., 2003).

Future Research Questions and Directions

Promising observational data, a strong argument for biological plausibility, and significant limitations of past RCTs support the need for additional research on the effects of statins and other lipid-lowering treatments in preventing cognitive decline and dementia. Intervention studies on statins have been conducted largely in populations with normal cognition and high vascular risk. Conducting future studies in other populations, such as adults with MCI and those at low vascular risk (e.g., normal cholesterol levels), and initiating interventions at midlife may expand understanding of the cognitive effects of lipid-lowering drugs. Moreover, little is known regarding the cognitive effects of other (nonstatin) lipid-lowering drugs, such as ezetimibe and fenofibrate, and this is another area in which more research may be valuable. The committee identified the following priority research questions:

• Which populations (considering, for example, age, cholesterol level and overall vascular risk, and baseline cognitive status) may benefit most from lipid-lowering treatments? Are any age groups at risk of being harmed by lipid lowering?
• Do other classes of lipid-lowering treatments, alone or in combination with statins, show potential to prevent cognitive decline and dementia if tested in studies that are sufficiently powered and of adequate duration?

Sleep Quality Interventions

Sleep disturbances, including difficulty falling or staying asleep, fragmented sleep, sleep-disordered breathing, and circadian rhythm disturbances, are common among the elderly and have been associated with cognitive decline (Yaffe et al., 2014). Among individuals with Alzheimer’s disease, sleep disruptions can be especially severe (Bliwise, 1993), and elevated brain beta-amyloid burden is associated with worse sleep quality (Brown et al., 2016; Spira et al., 2013, 2014).

Multiple factors associated with poor sleep quality also are associated

with cognitive decline and Alzheimer’s disease, including metabolic and inflammatory changes that lead to cardiovascular disease and diabetes (Landry and Liu-Ambrose, 2014; Mullington et al., 2009) and primary sleep disorders such as sleep apnea (Emamian et al., 2016). Chronic inflammation increases the risk for circadian dysregulation and cognitive decline (Landry and Liu-Ambrose, 2014), and intermittent hypoxia associated with sleep-disordered breathing may lead to neurodegeneration (Yang et al., 2013). Moreover, sleep plays a role in memory consolidation (Diekelmann and Born, 2010). Through the glymphatic system, sleep also plays an important role in clearing toxins such as beta-amyloid and tau from the brain (Cedernaes et al., 2016; Xie et al., 2013). Taken together, these converging lines of research suggest that interventions aimed at improving sleep quality and circadian regulation could have a role in preventing or slowing the progression of cognitive decline and dementia (Landry and Liu-Ambrose, 2014). Empirical evidence, however, is lacking, and the potential for reverse causality needs to be explored.

AHRQ Systematic Review Findings and Discussion

As summarized in Box 4-5, the AHRQ systematic review concluded that insufficient evidence exists to support the use of sleep interventions to prevent cognitive decline and dementia. However, only two RCTs of sleep interventions were identified in the AHRQ systematic review, and neither of these studies met the criteria for low to medium risk of bias. Furthermore, the interventions tested did not include sleep restriction and stimulus control, two components of behavioral interventions for insomnia that are considered the gold standard of insomnia treatment (McCurry, 2016).

Supplemental Information and Considerations

Although the AHRQ systematic review did not find sufficient evidence to indicate whether sleep interventions can prevent cognitive decline and

dementia, the substantial body of data supporting a link between sleep and cognition suggests that improving sleep quality could improve cognitive performance. A recent study using polysomnography to assess biophysical changes during sleep found that better sleep quality, when measured objectively, is associated with improvements in executive function in adults with insomnia (Wilckens et al., 2016). Cognitive-behavioral therapy for insomnia (CBTI) is among the most well-studied sleep interventions, but its effect on cognitive outcomes has not been well studied. Other potential interventions that have been evaluated in patients with dementia for improving sleep and cognitive function include light therapy (Forbes et al., 2014) and use of melatonin (Wade et al., 2014; Zisapel, 2001). Whether these interventions would have a role in preventing cognitive decline and dementia has not been determined.

Future Research Questions and Directions

Accumulating evidence from observational studies in humans and experimental studies in animal models supports a link between sleep disruptions and the pathogenesis of Alzheimer’s disease (Cedernaes et al., 2016), although reverse causality is a potential factor to be considered in future research. Given the urgency of identifying interventions that may prevent, slow, or delay the development of CATD, additional studies on this potential therapeutic approach are needed. A key question is whether the observed benefits of sleep for cognition translate into the delay or slowing of cognitive decline and the prevention, slowing, or delay of MCI and CATD. Answering this question will require the use of accurate, sensitive, and standardized measures of sleep quality and a better understanding of which cognitive domains to assess. Future research questions that can then be answered regarding sleep-based interventions include the following:

• Do interventions designed to improve sleep quality delay or slow cognitive decline in the long term and prevent dementia?
• What kinds of interaction effects are important to consider in studies of sleep interventions? How might the effect of improved sleep be accounted for in studies of other interventions that have known effects on cognition and sleep (e.g., physical activity)?
• How does sleep quality in midlife affect late-life cognitive outcomes?

Social Engagement Interventions

A growing body of evidence suggests that engaging in social activities may help prevent cognitive decline and dementia (IOM, 2015). Such evidence stems from observational studies on the cognitive impacts of social

isolation and loneliness (Holwerda et al., 2014; O’Luanaigh et al., 2012; Shankar et al., 2013), as well as observational (Brown et al., 2012) and intervention (Mortimer et al., 2012) studies on the cognitive benefits of participation in social activities. A variety of different mechanisms by which social engagement may be linked to cognitive decline and dementia have been proposed. They include direct neurobiological effects (e.g., neuroplasticity), as well as indirect effects such as diminished sleep quality, reduced physical activity, and increased risk of depression in those who are socially isolated (Cacioppo and Hawkley, 2009). Studies on social engagement can be challenging to design, as measurement of social activity is often subjective, and it is difficult to isolate the social aspects of activities from other aspects (e.g., cognitive stimulation) that also may affect cognition.

AHRQ Systematic Review Findings and Discussion

As summarized in Box 4-6, the AHRQ systematic review found that insufficient evidence exists to support a conclusion on the efficacy of interventions targeting social engagement in preventing cognitive decline and dementia. The one intervention study identified in this domain was designed to evaluate the effect of cognitive group social interactions (board games, discussions of newspaper articles) in adults with MCI, but this study was determined to be at high risk of bias.

Supplemental Information and Considerations

Although it is particularly difficult to disentangle the effects of social engagement from those of cognitively stimulating activities, studies have suggested that social interactions have positive effects on cognitive outcomes (Mortimer et al., 2012). One study comparing the effects of reasoning-based cognitive training and an intervention aimed at fostering creative problem solving in a socially complex, team-based competitive environment

showed that both approaches can improve cognitive performance, but in different cognitive domains (Stine-Morrow et al., 2014).

Future Research Questions and Directions

Priority research questions with respect to the potential role of social engagement interventions in preventing cognitive decline and dementia include the following:

• Which kinds of social activities might have the greatest impact on long-term cognitive outcomes?
• Are there specific interventions targeting increased social activity that reduce the risks for cognitive decline and dementia?

Vitamin B₁₂ Plus Folic Acid Supplementation

Supplemental B vitamins (B₆, B₁₂, and folate) are of interest as possible interventions for preventing cognitive decline and dementia based on their ability to lower blood homocysteine levels, which, when elevated, are associated with increased risk of cardio- and cerebrovascular disease, as well as poor cognitive outcomes (Beydoun et al., 2014; IOM, 2015). Blood homocysteine levels are known to increase with age and declining kidney function, but are determined largely by dietary B vitamin intake (Beydoun et al., 2014). Despite evidence linking vitamin B₁₂ deficiency with cognitive impairment (Moore et al., 2012), a previous review did not find strong evidence for benefits of B₁₂ supplementation (alone or in combination with other B vitamins) for cognitive function (Ontario Health Technology Advisory Committee, 2013).

AHRQ Systematic Review Findings and Discussion

Results from studies of B vitamin interventions included in the AHRQ systematic review were mixed for adults with normal cognition. As summarized in Box 4-7, the review found some indication of short-term improvement in Brief Cognitive Test performance for intervention groups in two RCTs (total N = 3,819) receiving vitamin B₁₂ plus folic acid compared with placebo (van der Zwaluw et al., 2014a; Walker et al., 2012). However, effect sizes were small, and follow-up periods were limited to 2 years, so the long-term implications of these results are unclear. The study by Walker and colleagues (2012) also found benefits for memory for two of three cognitive tests. Neither study showed benefits for performance in the areas of executive function, attention, and processing speed. Of note, in the study by van der Zwaluw and colleagues (2014a), adults with elevated homocysteine

levels were specifically recruited, so the study population had a higher risk of vitamin B deficiency relative to the general population. Two other studies in adults with normal cognition failed to show any benefit of vitamin B₁₂ combined with vitamin B₆ and folate compared with placebo (Andreeva et al., 2011; McMahon et al., 2006).

Supplemental Information and Considerations

Biomarker data also suggest a potential benefit of vitamin B₁₂ supplementation in individuals with a deficiency. An RCT published by Smith and colleagues (2010) showed that supplementation with B vitamins slowed the rate of brain atrophy in adults with MCI. The study used only surrogate neuroimaging markers and therefore was not included in the AHRQ systematic review, but those markers moved in a direction consistent with a favorable effect.

Results of the studies of Smith and colleagues (2010) and van der Zwaluw and colleagues (2014a), along with decades of negative trials in unselected populations, suggest that an approach targeting individuals with higher homocysteine levels may have value. Not only are elevated homocysteine levels associated with vascular risk, but they also may portend a subset of the population that is at higher risk for development of B₁₂ deficiency over time. It is well known that the prevalence of pernicious anemia and B₁₂ deficiency increases with age and that left untreated, they can cause neurodegeneration, including cognitive impairment (Andres and Serraj, 2012;

Kifle et al., 2009; Moore et al., 2012; Toh et al., 1997). Other studies that did not involve targeting a higher-risk group likely were offering treatment to individuals who, because of adequate nutrition and absorption of B₁₂ in particular, would not be likely to show a B vitamin–mediated beneficial effect. Given evidence from research on B₁₂ and folate showing the importance of accounting for initial deficits in these vitamins, it is important for future research on dietary supplements to control for baseline levels.

Future Research Questions and Directions

Future research on vitamin B₁₂ plus folic acid supplementation may be of most value if it can clarify whether the effects on cognitive performance generally are limited to those at higher risk of a deficiency. A higher-risk population could be selected for future studies based on higher measured homocysteine levels—for example, the top half of the distribution or potentially the top third or quartile to target an even higher-risk group. An alternative approach would be a simple but large pragmatic trial based on screening a large population in a real-world clinical setting and randomizing only those at risk of deficiency to receive vitamin B₁₂ plus folic acid or placebo. The following are priority questions for this research:

• Are cognitive outcomes associated with vitamin B₁₂ plus folic acid supplementation improved in a population at risk for a deficiency as compared with a population not at risk?
• Do the short-term improvements in cognitive performance observed for vitamin B₁₂ plus folic acid supplementation translate into delay or slowing of cognitive decline and reduced risk of dementia?

LOWEST-PRIORITY INTERVENTIONS FOR FUTURE RESEARCH

This section provides a brief overview of those interventions for which the AHRQ systematic review found no evidence of any benefit and some low-strength evidence indicating that the intervention does not prevent cognitive decline or dementia and, in one case, may in fact increase the risk of MCI or dementia. Based on these findings, the committee believes these interventions should be the lowest priority for future research.

Interventions with Evidence Suggesting Detrimental Effects on Cognition

For most hormone therapy interventions included in the AHRQ systematic review, evidence on cognitive impacts is insufficient to draw conclusions regarding their priority for future research. However, estrogen-containing hormone therapy interventions were given special consideration in the

AHRQ systematic review because of their observed detrimental effects on cognition in women aged 65 or older (as summarized in Box 4-8).

Much of the evidence on the cognitive effects of hormone replacement therapy originates from substudies of the large and long-duration Women’s Health Initiative RCT. The Women’s Health Initiative Memory Study (WHIMS) and the Women’s Health Initiative Study of Cognitive Aging (WHISCA) examined effects of hormone replacement therapies that included conjugated equine estrogen on cognition in women aged 65 or older. These studies found that such medications increased the overall risk of dementia by 76 percent and resulted in a small average relative deficit in cognitive function that persisted for years after the cessation of therapy (Espeland et al., 2017b; Shumaker et al., 2004). Furthermore, significantly lower frontal lobe volumes (a marker of brain atrophy) were observed in women assigned to hormone therapy in the WHIMS study. Conjugated equine estrogen therapies may be particularly harmful for older women with diabetes (Espeland et al., 2015a,b). In addition to these cognitive effects, increased risk of stroke was observed in the parent Women’s Health Initiative clinical trial (Manson et al., 2013).

Three recent well-powered RCTs have examined whether various hormone therapy regimens affect cognitive function in women nearer to the time of their menopausal transition: the Women’s Health Initiative Study of Younger Women (Espeland et al., 2013, 2017b), the Kronos Early Estrogen Prevention Study (Gleason et al., 2015; Kantarci et al., 2016), and the Early vs. Late Intervention Trial with Estradiol (Henderson et al., 2016). None

of these studies found any cognitive benefit of any of the hormone therapy regimens, and there was some evidence of increased brain atrophy linked to one hormone preparation (Kantarci et al., 2016). Of note, no studies have examined whether hormone therapy, if begun during the menopausal transition rather than following menopause, affects cognitive function.

In conclusion, although hormone therapy remains the recommended treatment for menopausal symptoms, current evidence is that it provides no cognitive benefit for younger women, and therapies based on conjugated equine estrogen may be harmful for women aged 65 or older, increasing their risk for dementia and brain atrophy. In addition, a number of studies have found that hormone therapies may increase women’s risk for stroke. The current evidence suggests that hormone therapies based on estrogen or estrogen plus progestin should be deprioritized in future research aimed at identifying interventions that prevent cognitive decline and dementia in older women.

Interventions with Some Evidence Suggesting No Benefit

Some low-strength evidence from RCTs suggests that nonsteroidal antiinflammatory drugs, vitamin E, gingko biloba, and medications belonging to the class of antidementia drugs known as acetylcholinesterase inhibitors do not prevent or delay dementia or improve cognitive function. Key findings from the AHRQ systematic review for each of these interventions are summarized in Box 4-9. Although the limitations of existing studies make it difficult to definitively rule out possible benefits of these interventions under certain conditions (e.g., in specific subpopulations or in combination with other interventions), the committee believes that priorities for future intervention research are the more promising areas described above.

With regard to the nutritional supplements included in Box 4-9—gingko biloba and vitamin E—the committee notes that these supplements are widely marketed, with manufacturers claiming a variety of potential health benefits. While a review of health effects attributable to these supplements outside of the cognitive domain is beyond the scope of this report, and there is little evidence to suggest they may be harmful, the nontrivial cost of their purchase may not be justified if their intended use is to prevent cognitive decline or bolster cognitive performance. As discussed earlier in this chapter, however, the committee supports additional study of the cognitive effects of diet more broadly, even if attempts to tease out the potential benefits of individual nutritional components have been largely unsuccessful.

Intervention studies on acetylcholinesterase inhibitors have failed to provide any evidence that these drugs are effective at preventing further cognitive decline and progression to dementia in people with MCI. There

are currently five drugs approved by the U.S. Food and Drug Administration to treat the cognitive symptoms of Alzheimer’s disease—four cholinesterase inhibitors⁶ and memantine, an N-methyl-D-aspartate (NMDA)-receptor antagonist (Cummings et al., 2014). None of these drugs treats the underlying cause of Alzheimer’s disease, nor do they slow disease progression (Cummings et al., 2016a; Schneider and Sano, 2009). No new Alzheimer’s drug has been approved since 2003 (Cummings et al., 2014). However, as discussed earlier in this chapter, the search for new antidementia treatments that can delay onset or slow progression of cognitive impairment and dementia remains a priority for future research.

RECOMMENDATIONS

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⁶ Only three cholinesterase inhibitors are commonly used to treat dementia symptoms, as one—tacrine—has been associated with toxicity and significant adverse effects (Winker, 1994).

FINAL THOUGHTS

While the committee recognizes that well-conducted, rigorous, generalizable RCTs are the gold standard for demonstrating the effectiveness of interventions for preventing common conditions such as ARCD and CATD, there are references throughout this report to the challenges of implementing RCTs to test the value of interventions and behavioral changes for preventing or delaying such conditions. For example, the potential benefits of higher levels of education and socioeconomic well-being may have effects throughout the life course, from birth through the long process of brain aging, but these effects cannot be evaluated in an RCT. Alzheimer’s-related brain changes are known to appear well before symptoms manifest and, like the unexpected coronary artery disease seen in autopsies of Korean War veterans (Enos et al., 1953), may even be present in young adults. Is there a conceivable way to study people this young for an illness that typically develops many decades later?

An added challenge is that many of the interventions that show prom-

ise today, such as better control of hypertension and diabetes and regular physical activity, have widely accepted health benefits and are broadly prescribed. Similarly, while smoking has been shown to be a risk factor for dementia, it is difficult to imagine an ethically acceptable long-term RCT that would include an untreated control group and could meet the stringent quality criteria of the evidence-based practice center. Potential solutions to these challenges include using evidence from life-course epidemiology cohort studies employing the most rigorous methods possible, and possibly from studies aimed at improving adherence to and adoption of such treatments as diabetes management in which the “control” group would be usual care. There are no easy answers to these challenges, and the National Institute on Aging and other institutes and organizations—in collaboration with researchers with expertise in cognitive decline and dementia—will need to continue to grapple with the question of what kinds of research and outcomes constitute evidence rigorous enough to provide clear support for public health messaging.

The subject of this report is a vibrant, dynamic research area whose story is not complete. The fact that the report does not strongly support a public health campaign focused on actively promoting adoption of any type of intervention should not be taken to reflect a lack of progress or prospects for preventing or delaying the discussed conditions. Although inconclusive, clinical trials and other studies have yielded encouraging data for some interventions, and the public should have access to this information to inform choices on how to invest time and resources to maintain brain health with aging. Despite the challenges noted above, RCT data will continue to form a critical source of evidence in this field. Trials in this area are under way and planned, funded by the National Institutes of Health and others, and more evidence is emerging all the time. As the results of these trials become available, it will be critical to assess them with an eye to updating the recommendations presented in this report for communicating with the public. Future intervention trials that build on advances in understanding of the biological basis of CATD and incorporate cutting-edge designs and the methodological recommendations presented herein will generate a more comprehensive, stronger evidence base. There is good cause for hope that in the next several years, much more will be known about how to prevent cognitive decline and dementia.

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