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.

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.

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).

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).

BOX 4-1

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON DIABETES MEDICATION TREATMENT.

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.

BOX 4-2

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON DEPRESSION INTERVENTIONS.

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 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.

BOX 4-3

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON DIET INTERVENTIONS.

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.

BOX 4-4

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON LIPID-LOWERING TREATMENT.

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).

BOX 4-5

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON SLEEP QUALITY INTERVENTIONS.

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.

BOX 4-6

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON SOCIAL ENGAGEMENT INTERVENTIONS.

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).

BOX 4-7

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON B VITAMINS.

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).

BOX 4-8

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON HORMONE THERAPY.

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.

BOX 4-9

AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS RELATED TO INTERVENTIONS THAT SHOWED SOME EVIDENCE SUGGESTING NO BENEFIT.

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

CONCLUSION: Before public health messaging strongly encourages adoption of cognitive training, blood pressure management for people with hypertension, and increased physical activity solely for the purpose of maintaining cognitive function, additional research is needed to further understand and gain confidence in the effectiveness of these interventions. Emerging data from multimodal intervention studies suggest there may be value to evaluating each of these interventions alone and in combination. Some large studies already under way may help address these questions.

CONCLUSION: There is insufficient evidence with which to assess the effectiveness of the following interventions in preventing cognitive decline and dementia: diabetes treatment, dietary interventions, depression treatment, lipid-lowering treatment, sleep quality interventions, social engagement interventions, and vitamin B₁₂ plus folic acid supplementation. Emerging data and/or biological arguments suggest that these interventions could be considered, but additional research is needed before a decision can be made as to whether they should be included in public health messaging. Emerging data from multimodal intervention studies suggest there may be value to evaluating each of these interventions alone and in combination. In addition, it will be important to explore new targets—beyond amyloid and tau—for antidementia drug development.

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 promise 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.

REFERENCES

• ADA (American Diabetes Association). Diabetes Care. Suppl 1. Vol. 39. 2016. Professional practice committee for the standards of medical care in diabetes—2016; pp. S107–S108. [PubMed: 26696673]
• ADA. Diabetes Care. Suppl 1. Vol. 40. 2017. Obesity management for the treatment of type 2 diabetes; pp. S57–S63. [PubMed: 27979894]
• American College of Cardiology. Heart Outcomes Prevention Evaluation-3—HOPE-3. 2016. [February 8, 2017]. http://www​.acc.org/latest-in-cardiology​/clinical-trials​/2016/03/25/16/27/hope-3 .
• Andreeva VA, Kesse-Guyot E, Barberger-Gateau P, Fezeu L, Hercberg S, Galan P. American Journal of Clinical Nutrition. 1. Vol. 94. 2011. Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: Ancillary findings from the SU.FOL.OM3 randomized trial; pp. 278–286. [PubMed: 21593490]
• Andres E, Serraj K. Journal of Blood Medicine. Vol. 3. 2012. Optimal management of pernicious anemia; pp. 97–103. [PMC free article: PMC3441227] [PubMed: 23028239]
• Andrieu S, Guyonnet S, Coley N, Cantet C, Bonnefoy M, Bordes S, Bories L, Cufi MN, Dantoine T, Dartigues JF, Desclaux F, Gabelle A, Gasnier Y, Pesce A, Sudres K, Touchon J, Robert P, Rouaud O, Legrand P, Payoux P, Caubere JP, Weiner M, Carrié I, Ousset PJ, Vellas B., MAPT Study Group. The Lancet Neurology. 5. Vol. 16. 2017. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial; pp. 377–389. [PubMed: 28359749]
• Atreja A, Bellam N, Levy SR. Medscape General Medicine. 1. Vol. 7. 2005. Strategies to enhance patient adherence: Making it simple; p. 4. [PMC free article: PMC1681370] [PubMed: 16369309]
• Barnard N, Bunner A, Agarwal U. Neurobiology of Aging. Suppl 2. Vol. 35. 2014. Saturated and trans fats and dementia: A systematic review; pp. S65–S73. [PubMed: 24916582]
• Barnes D, Yaffe K. The Lancet Neurology. 9. Vol. 10. 2011. The projected impact of risk factor reduction on Alzheimer's disease prevalence; pp. 819–828. [PMC free article: PMC3647614] [PubMed: 21775213]
• Barnes DE, Santos-Modesitt W, Poelke G, Kramer AF, Castro C, Middleton LE, Yaffe K. JAMA Internal Medicine. 9. Vol. 173. 2013. The Mental Activity and eXercise (MAX) trial: A randomized controlled trial to enhance cognitive function in older adults; pp. 797–804. [PMC free article: PMC5921904] [PubMed: 23545598]
• Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. BMC Public Health. Vol. 14. 2014. Epidemiologic studies of modifiable factors associated with cognition and dementia: Systematic review and meta-analysis; p. 643. [PMC free article: PMC4099157] [PubMed: 24962204]
• Bliwise DL. Sleep. 1. Vol. 16. 1993. Sleep in normal aging and dementia; pp. 40–81. [PubMed: 8456235]
• Blumenthal JA, Smith PJ, Welsh-Bohmer K, Babyak MA, Browndyke J, Lin PH, Doraiswamy PM, Burke J, Kraus W, Hinderliter A, Sherwood A. Contemporary Clinical Trials. 1. Vol. 34. 2013. Can lifestyle modification improve neurocognition? Rationale and design of the ENLIGHTEN clinical trial; pp. 60–69. [PMC free article: PMC3800162] [PubMed: 23000080]
• Bromfield SG, Bowling CB, Tanner RM, Peralta CA, Odden MC, Oparil S, Muntner P. Journal of Clinical Hypertension (Greenwich, Conn.). 4. Vol. 16. 2014. Trends in hypertension prevalence, awareness, treatment, and control among U.S. adults 80 years and older, 1988-2010; pp. 270–276. [PMC free article: PMC8186288] [PubMed: 24621268]
• Brown BM, Rainey-Smith SR, Villemagne VL, Weinborn M, Bucks RS, Sohrabi HR, Laws SM, Taddei K, Macaulay SL, Ames D, Fowler C, Maruff P, Masters CL, Rowe CC, Martins RN. Sleep. 5. Vol. 39. 2016. The relationship between sleep quality and brain amyloid burden; pp. 1063–1068. [PMC free article: PMC4835305] [PubMed: 27091528]
• Brown CL, Gibbons LE, Kennison RF, Robitaille A, Lindwall M, Mitchell MB, Shirk SD, Atri A, Cimino CR, Benitez A, MacDonald SWS, Zelinski EM, Willis SL, Schaie KW, Johansson B, Dixon RA, Mungas DM, Hofer SM, Piccinin AM. Journal of Aging Research. Vol. 2012. 2012. Social activity and cognitive functioning over time: A coordinated analysis of four longitudinal studies; p. 287438. [PMC free article: PMC3444000] [PubMed: 22991665]
• Budur K, Welsh-Bohmer K, Burns DK, Chiang C, O'Neil J, Runyan G, Culp M, Crenshaw DG, Lutz MW, Metz CA, Saunders AM, Yarbrough D, Yarnall D, Lai E, Brannan SK, Roses AD. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 7, Suppl. Vol. 11. 2015. Progress in the TOMMORROW Study: A pharmacogenetics supported clinical trial to delay onset of mild cognitive impairment due to Alzheimer's disease with low-dose pioglitazone; p. P515.
• Butters MA, Whyte EM, Nebes RD, Begley AE, Dew MA, Mulsant BH, Zmuda MD, Bhalla R, Meltzer CC, Pollock BG, Reynolds CF III, Becker JT. Archives of General Psychiatry. 6. Vol. 61. 2004. The nature and determinants of neuropsychological functioning in late-life depression; pp. 587–595. [PubMed: 15184238]
• Byers AL, Yaffe K. Nature Reviews Neurology. 6. Vol. 7. 2011. Depression and risk of developing dementia; pp. 323–331. [PMC free article: PMC3327554] [PubMed: 21537355]
• Cacioppo JT, Hawkley LC. Trends in Cognitive Sciences. 10. Vol. 13. 2009. Perceived social isolation and cognition; pp. 447–454. [PMC free article: PMC2752489] [PubMed: 19726219]
• Campbell NL, Boustani MA, Skopelja EN, Gao S, Unverzagt FW, Murray MD. The American Journal of Geriatric Pharmacotherapy. 3. Vol. 10. 2012. Medication adherence in older adults with cognitive impairment: A systematic evidence-based review; pp. 165–177. [PubMed: 22657941]
• Carlson MC, Saczynski JS, Rebok GW, Seeman T, Glass TA, McGill S, Tielsch J, Frick KD, Hill J, Fried LP. Gerontologist. 6. Vol. 48. 2008. Exploring the effects of an “everyday” activity program on executive function and memory in older adults: Experience Corps; pp. 793–801. [PubMed: 19139252]
• Cedernaes J, Osorio RS, Varga AW, Kam K, Schioth HB, Benedict C. Sleep Medicine Reviews. Vol. 31. 2016. Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease; pp. 102–111. [PMC free article: PMC4981560] [PubMed: 26996255]
• Chalmers J, Cooper ME. New England Journal of Medicine. 15. Vol. 359. 2008. UKPDS and the legacy effect; pp. 1618–1620. [PubMed: 18843126]
• Cheng G, Huang C, Deng H, Wang H. Internal Medicine. 5. Vol. 42. 2012. Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies; pp. 484–491. [PubMed: 22372522]
• Craft S, Watson GS. The Lancet Neurology. 3. Vol. 3. 2004. Insulin and neurodegenerative disease: Shared and specific mechanisms; pp. 169–178. [PubMed: 14980532]
• Cukierman-Yaffe T, Bosch J, Diaz R, Dyal L, Hancu N, Hildebrandt P, Lanas F, Lewis BS, Marre M, Yale JF, Yusuf S, Gerstein HC. The Lancet Diabetes & Endocrinology. 7. Vol. 2. 2014. Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: A substudy of the ORIGIN trial; pp. 562–572. [PubMed: 24898834]
• Culang ME, Sneed JR, Keilp JG, Rutherford BR, Pelton GH, Devanand DP, Roose SP. American Journal of Geriatric Psychiatry. 10. Vol. 17. 2009. Change in cognitive functioning following acute antidepressant treatment in late-life depression; pp. 881–888. [PMC free article: PMC3852681] [PubMed: 19916207]
• Cummings J, Morstorf T, Zhong K. Alzheimer's Research and Therapy. 37. Vol. 6. 2014. Alzheimer's disease drug-development pipeline: Few candidates, frequent failures. [PMC free article: PMC4095696] [PubMed: 25024750]
• Cummings J, Morstorf T, Lee G. Alzheimer's & Dementia: Translational Research and Clinical Interventions. 4. Vol. 2. 2016a. Alzheimer's drug-development pipeline: 2016; pp. 222–232. [PMC free article: PMC5651348] [PubMed: 29067309]
• Cummings J, Aisen PS, Dubois B, Frolich L, Jack CR Jr., Jones RW, Morris JC, Raskin J, Dowsett SA, Scheltens P. Alzheimer's Research & Therapy. 39. Vol. 8. 2016b. Drug development in Alzheimer's disease: The path to 2025. [PMC free article: PMC5028936] [PubMed: 27646601]
• Dalton AM, Wareham N, Griffin S, Jones AP. SSM—Population Health. Vol. 2. 2016. Neighbourhood greenspace is associated with a slower decline in physical activity in older adults: A prospective cohort study; pp. 683–691. [PMC free article: PMC5165047] [PubMed: 28018960]
• Diekelmann S, Born J. Nature Reviews Neuroscience. 2. Vol. 11. 2010. The memory function of sleep; pp. 114–126. [PubMed: 20046194]
• Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF. The British Journal of Psychiatry. 5. Vol. 202. 2013. Late-life depression and risk of vascular dementia and Alzheimer's disease: Systematic review and meta-analysis of community-based cohort studies; pp. 329–335. [PMC free article: PMC3640214] [PubMed: 23637108]
• Emamian F, Khazaie H, Tahmasian M, Leschziner GD, Morrell MJ, Hsiung GY, Rosenzweig I, Sepehry AA. Frontiers in Aging Neuroscience. Vol. 8. 2016. The association between obstructive sleep apnea and Alzheimer's disease: A meta-analysis perspective; p. 78. [PMC free article: PMC4828426] [PubMed: 27148046]
• Enos WF, Holmes RH, Beyer J. Journal of the American Medical Association. 12. Vol. 152. 1953. Coronary disease among United States soldiers killed in action in Korea; pp. 1090–1093. [PubMed: 13052433]
• Espeland MA, Shumaker SA, Leng I, Manson JE, Brown CM, LeBlanc ES, Vaughan L, Robinson J, Rapp SR, Goveas JS, Wactawski-Wende J, Stefanick ML, Li W, Resnick SM. JAMA Internal Medicine. 15. Vol. 173. 2013. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years; pp. 1429–1436. [PMC free article: PMC3844547] [PubMed: 23797469]
• Espeland MA, Rapp SR, Bray GA, Houston DK, Johnson KC, Kitabchi AE, Hergenroeder AL, Williamson J, Jakicic JM, van Dorsten B, Kritchevsky SB. Journals of Gerontology, Series A: Biological Sciences & Medical Sciences. 9. Vol. 69. 2014. Long-term impact of behavioral weight loss intervention on cognitive function; pp. 1101–1108. [PMC free article: PMC4158413] [PubMed: 24619151]
• Espeland MA, Brinton RD, Hugenschmidt C, Manson JE, Craft S, Yaffe K, Weitlauf J, Vaughan L, Johnson KC, Padula CB, Jackson RD, Resnick SM. Diabetes Care. 12. Vol. 38. 2015a. Impact of type 2 diabetes and postmenopausal hormone therapy on incidence of cognitive impairment in older women; pp. 2316–2324. [PMC free article: PMC4657616] [PubMed: 26486190]
• Espeland MA, Brinton RD, Manson JE, Yaffe K, Hugenschmidt C, Vaughan L, Craft S, Edwards BJ, Casanova R, Masaki K, Resnick SM. Neurology. 13. Vol. 85. 2015b. Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes; pp. 1131–1138. [PMC free article: PMC4603880] [PubMed: 26163429]
• Espeland MA, Luchsinger JA, Baker LD, Neiberg R, Kahn SE, Arnold SE, Wing RR, Blackburn GL, Bray G, Evans M, Hazuda HP, Jeffrey RW, Wilson VM, Clark JM, Coday M, Demos-McDermott K, Foreyt JP, Greenway F, Hill JO, Horton ES, Jakicic JM, Johnson KC, Knowler WC, Lewis CE, Nathan DM, Peters A, Pi-Sunyer X, Wadden TA, Rapp SR. Neurology. 21. Vol. 88. 2017a. Effect of long-term intensive lifestyle intervention on prevalence of cognitive impairment; pp. 2026–2035. [PMC free article: PMC5440245] [PubMed: 28446656]
• Espeland MA, Rapp SR, Manson JE, Goveas JS, Shumaker SA, Hayden KM, Weitlauf JC, Gaussoin SA, Baker LD, Padula CB, Hou L, Resnick SM. Journals of Gerontology, Series A: Biological Sciences & Medical Sciences. 6. Vol. 72. 2017b. Long-term effects on cognitive trajectories of postmenopausal hormone therapy in two age groups; pp. 838–845. [PMC free article: PMC6075542] [PubMed: 27506836]
• Etgen T, Sander D, Bickel H, Forstl H. Deutsches Ärzteblatt International. 44. Vol. 108. 2011. Mild cognitive impairment and dementia: The importance of modifiable risk factors; pp. 743–750. [PMC free article: PMC3226957] [PubMed: 22163250]
• Fitó M, Guxens M, Corella D, Sáez G, Estruch R, de la Torre R, Francés F, Cabezas C, López-Sabater Mdel C, Marrugat J, García-Arellano A, Arós F, Ruiz-Gutierrez V, Ros E, Salas-Salvadó J, Fiol M, Solá R, Covas MI. Archives of Internal Medicine. 11. Vol. 167. 2007. Effect of a traditional Mediterranean diet on lipoprotein oxidation: A randomized controlled trial; pp. 1195–1203. [PubMed: 17563030]
• Forbes D, Blake CM, Thiessen EJ, Peacock S, Hawranik P. Cochrane Database of Systematic Reviews. Vol. 2. 2014. Light therapy for improving cognition, activities of daily living, sleep, challenging behaviour, and psychiatric disturbances in dementia; p. CD003946. [PubMed: 24574061]
• Gerstein HC, Miller ME, Byington RP, Goff DC Jr., Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr., Probstfield JL, Simons-Morton DG, Friedewald WT. New England Journal of Medicine. 24. Vol. 358. 2008. Effects of intensive glucose lowering in type 2 diabetes; pp. 2545–2559. [PMC free article: PMC4551392] [PubMed: 18539917]
• Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. New England Journal of Medicine. 4. Vol. 367. 2012. Basal insulin and cardiovascular and other outcomes in dysglycemia; pp. 319–328. [PubMed: 22686416]
• Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR, Neal-Perry G, Santoro NF, Taylor HS, Black DM, Budoff MJ, Hodis HN, Naftolin F, Harman SM, Asthana S. PLoS Medicine/Public Library of Science. 6. Vol. 12. 2015. Effects of hormone therapy on cognition and mood in recently postmenopausal women: Findings from the randomized, controlled keeps-cognitive and affective study; p. e1001833. [PMC free article: PMC4452757] [PubMed: 26035291]
• Gottesman RF. Preventing dementia and cognitive impairment—vascular factors, diabetes, and obesity: Observational evidence. Washington, DC: Oct 25, 2016. Paper presented at Preventing Dementia and Cognitive Impairment: A Workshop.
• Goveas JS, Hogan PE, Kotchen JM, Smoller JW, Denburg NL, Manson JE, Tummala A, Mysiw WJ, Ockene JK, Woods NF, Espeland MA, Wassertheil-Smoller S. International Psychogeriatrics. 8. Vol. 24. 2012. Depressive symptoms, antidepressant use, and future cognitive health in postmenopausal women: The Women's Health Initiative Memory Study; pp. 1252–1264. [PMC free article: PMC5800401] [PubMed: 22301077]
• Goveas JS, Espeland MA, Hogan PE, Tindle HA, Shih RA, Kotchen JM, Robinson JG, Barnes DE, Resnick SM. Journal of Geriatric Psychiatry and Neurology. 2. Vol. 27. 2014. Depressive symptoms and longitudinal changes in cognition: Women's Health Initiative Study of Cognitive Aging; pp. 94–102. [PMC free article: PMC4433445] [PubMed: 24584465]
• Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Journal of Neurology, Neurosurgery, and Psychiatry. 1. Vol. 80. 2009. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study; pp. 13–17. [PubMed: 18931004]
• Hardy JA, De Strooper B. Brain. 4. Vol. 140. 2017. Alzheimer's disease: Where next for anti-amyloid therapies? pp. 853–855. [PubMed: 28375461]
• Hardy JA, Higgins GA. Science. 5054. Vol. 256. 1992. Alzheimer's disease: The amyloid cascade hypothesis; pp. 184–185. [PubMed: 1566067]
• Harrison SL, Stephan BC, Siervo M, Granic A, Davies K, Wesnes KA, Kirkwood TB, Robinson L, Jagger C. Journal of the American Geriatrics Society. 4. Vol. 63. 2015. Is there an association between metabolic syndrome and cognitive function in very old adults? The Newcastle 85+ Study; pp. 667–675. [PubMed: 25850570]
• Hars M, Herrmann FR, Gold G, Rizzoli R, Trombetti A. Age & Ageing. 2. Vol. 43. 2014. Effect of music-based multitask training on cognition and mood in older adults; pp. 196–200. [PubMed: 24212920]
• Heart Protection Study Collaborative Group. The Lancet. 9326. Vol. 360. 2002. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial; pp. 7–22. [PubMed: 12114036]
• Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Kono N, Dustin L, Allayee H, Mack WJ. Neurology. 7. Vol. 87. 2016. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis; pp. 699–708. [PMC free article: PMC4999165] [PubMed: 27421538]
• Hildreth KL, Van Pelt RE, Moreau KL, Grigsby J, Hoth KF, Pelak V, Anderson CA, Parnes B, Kittelson J, Wolfe P, Nakamura T, Linnebur SA, Trujillo JM, Aquilante CL, Schwartz RS. Dementia and Geriatric Cognitive Disorders Extra. 1. Vol. 5. 2015. Effects of pioglitazone or exercise in older adults with mild cognitive impairment and insulin resistance: A pilot study; pp. 51–63. [PMC free article: PMC4361908] [PubMed: 25852732]
• Holwerda TJ, Deeg DJ, Beekman AT, van Tilburg TG, Stek ML, Jonker C, Schoevers RA. Journal of Neurology, Neurosurgery, and Psychiatry. 2. Vol. 85. 2014. Feelings of loneliness, but not social isolation, predict dementia onset: Results from the Amsterdam Study of the Elderly (AMSTEL) pp. 135–142. [PubMed: 23232034]
• IOM (Institute of Medicine). Cognitive aging: Progress in understanding and opportunities for action. Washington, DC: The National Academies Press; 2015. [PubMed: 25879131]
• Jobe JB, Smith DM, Ball K, Tennstedt SL, Marsiske M, Willis SL, Rebok GW, Morris JN, Helmers KF, Leveck MD, Kleinman K. Controlled Clinical Trials. 4. Vol. 22. 2001. ACTIVE: A cognitive intervention trial to promote independence in older adults; pp. 453–479. [PMC free article: PMC2916177] [PubMed: 11514044]
• Kane RL, Butler M, Fink HA, Brasure M, Davila H, Desai P, Jutkowitz E, McCreedy E, Nelson V, McCarten JR, Calvert C, Ratner E, Hemmy L, Barclay T. Interventions to prevent age-related cognitive decline, mild cognitive impairment, and clinical Alzheimer's-type dementia. Comparative effectiveness review 188. Rockville, MD: Agency for Healthcare Research and Quality; 2017. [PubMed: 28759193]
• Kantarci K, Lowe VJ, Lesnick TG, Tosakulwong N, Bailey KR, Fields JA, Shuster LT, Zuk SM, Senjem ML, Mielke MM, Gleason C, Jack CR Jr., Rocca WA, Miller VM. Journal of Alzheimer's Disease. 2. Vol. 53. 2016. Early postmenopausal transdermal 17-beta-estradiol therapy and amyloid-beta deposition; pp. 547–556. [PMC free article: PMC4955514] [PubMed: 27163830]
• Kifle L, Ortiz D, Shea TB. Journal of Alzheimer's Disease. 3. Vol. 16. 2009. Deprivation of folate and B12 increases neurodegeneration beyond that accompanying deprivation of either vitamin alone; pp. 533–540. [PubMed: 19276548]
• Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. BMJ. 7300. Vol. 322. 2001. Midlife vascular risk factors and Alzheimer's disease in later life: Longitudinal, population based study; pp. 1447–1451. [PMC free article: PMC32306] [PubMed: 11408299]
• Krell-Roesch J, Vemuri P, Pink A, Roberts RO, Stokin GB, Mielke MM, Christianson TJ, Knopman DS, Petersen RC, Kremers WK, Geda YE. JAMA Neurology. 3. Vol. 74. 2017. Association between mentally stimulating activities in late life and the outcome of incident mild cognitive impairment, with an analysis of the APOE ε4 genotype; pp. 332–338. [PMC free article: PMC5473779] [PubMed: 28135351]
• Landry GJ, Liu-Ambrose T. Frontiers in Aging Neuroscience. Vol. 6. 2014. Buying time: A rationale for examining the use of circadian rhythm and sleep interventions to delay progression of mild cognitive impairment to Alzheimer's disease; p. 325. [PMC free article: PMC4259166] [PubMed: 25538616]
• Larson EB, Yaffe K, Langa KM. New England Journal of Medicine. 24. Vol. 369. 2013. New insights into the dementia epidemic; pp. 2275–2277. [PMC free article: PMC4130738] [PubMed: 24283198]
• Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, Sullivan M, Horowitz KR, Ding J, Marcovina S, Lovato LC, Lovato J, Margolis KL, O'Connor P, Lipkin EW, Hirsch J, Coker L, Maldjian J, Sunshine JL, Truwit C, Davatzikos C, Bryan RN. The Lancet Neurology. 11. Vol. 10. 2011. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): A randomised open-label substudy; pp. 969–977. [PMC free article: PMC3333485] [PubMed: 21958949]
• Lee AL, Ogle WO, Sapolsky RM. Bipolar Disorders. 2. Vol. 4. 2002. Stress and depression: Possible links to neuron death in the hippocampus; pp. 117–128. [PubMed: 12071509]
• Lonn E, Bosch J, Pogue J, Avezum A, Chazova I, Dans A, Diaz R, Fodor GJ, Held C, Jansky P, Keltai M, Keltai K, Kunti K, Kim JH, Leiter L, Lewis B, Liu L, Lopez-Jaramillo P, Pais P, Parkhomenko A, Peters RJ, Piegas LS, Reid CM, Sliwa K, Toff WD, Varigos J, Xavier D, Yusoff K, Zhu J, Dagenais G, Yusuf S. Canadian Journal of Cardiology. 3. Vol. 32. 2016. Novel approaches in primary cardiovascular disease prevention: The HOPE-3 trial rationale, design, and participants' baseline characteristics; pp. 311–318. [PubMed: 26481083]
• Luchsinger JA. Journal of Alzheimer's Disease. 3. Vol. 20. 2010. Type 2 diabetes, related conditions, in relation and dementia: An opportunity for prevention? pp. 723–736. [PubMed: 20413862]
• Luchsinger JA, Palmas W, Teresi JA, Silver S, Kong J, Eimicke JP, Weinstock RS, Shea S. Journal of Nutrition, Health & Aging. 6. Vol. 15. 2011. Improved diabetes control in the elderly delays global cognitive decline; pp. 445–449. [PMC free article: PMC3328757] [PubMed: 21623465]
• Luchsinger JA, Lehtisalo J, Lindstrom J, Ngandu T, Kivipelto M, Ahtiluoto S, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Eriksson JG, Uusitupa M, Tuomilehto J. Diabetes Research and Clinical Practice. 3. Vol. 108. 2015. Cognition in the Finnish Diabetes Prevention Study; pp. e63–e66. [PubMed: 25799080]
• Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, Ichise M, Manly J, Devanand DP, Bagiella E. Journal of Alzheimer's Disease. 2. Vol. 51. 2016. Metformin in amnestic mild cognitive impairment: Results of a pilot randomized placebo controlled clinical trial; pp. 501–514. [PMC free article: PMC5079271] [PubMed: 26890736]
• Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O'Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Journal of the American Medical Association. 13. Vol. 310. 2013. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials; pp. 1353–1368. [PMC free article: PMC3963523] [PubMed: 24084921]
• Martin CK, Anton SD, Han H, York-Crowe E, Redman LM, Ravussin E, Williamson DA. Rejuvenation Research. 2. Vol. 10. 2007. Examination of cognitive function during six months of calorie restriction: Results of a randomized controlled trial; pp. 179–190. [PMC free article: PMC2664681] [PubMed: 17518698]
• Martinez-Lapiscina EH, Clavero P, Toledo EE, Estruch R, Salas-Salvado J, San Julian B, Sanchez-Tainta A, Ros E, Valls-Pedret C, Martinez-Gonzalez MA. Journal of Neurology, Neurosurgery, and Psychiatry. 12. Vol. 84. 2013. Mediterranean diet improves cognition: The PREDIMED-NAVARRA randomised trial; pp. 1318–1325. [PubMed: 23670794]
• McCurry S. Interventions on lifestyle and social support factors: Sleep quality and disorders. Washington, DC: Oct 25, 2016. Paper presented at Preventing Dementia and Cognitive Impairment: A Workshop.
• McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. New England Journal of Medicine. 26. Vol. 354. 2006. A controlled trial of homocysteine lowering and cognitive performance; pp. 2764–2772. [PubMed: 16807413]
• Mitjavila MT, Fandos M, Salas-Salvadó J, Covas MI, Borrego S, Estruch R, Lamuela-Raventós R, Corella D, Martínez-Gonzalez MÁ, Sánchez JM, Bulló M, Fitó M, Tormos C, Cerdá C, Casillas R, Moreno JJ, Iradi A, Zaragoza C, Chaves J, Sáez GT. Clinical Nutrition. 2. Vol. 32. 2013. The Mediterranean diet improves the systemic lipid and DNA oxidative damage in metabolic syndrome individuals. A randomized, controlled, trial; pp. 172–178. [PubMed: 22999065]
• Moll van Charante EP, Richard E, Eurelings LS, van Dalen JW, Ligthart SA, van Bussel EF, Hoevenaar-Blom MP, Vermeulen M, van Gool WA. The Lancet. 10046. Vol. 388. 2016. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (PreDIVA): A cluster-randomised controlled trial; pp. 797–805. [PubMed: 27474376]
• Moore E, Mander A, Ames D, Carne R, Sanders K, Watters D. International Psychogeriatrics. 4. Vol. 24. 2012. Cognitive impairment and vitamin B12: A review; pp. 541–556. [PubMed: 22221769]
• Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL, Bennett DA, Aggarwal NT. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 9. Vol. 11. 2015a. MIND diet slows cognitive decline with aging; pp. 1015–1022. [PMC free article: PMC4581900] [PubMed: 26086182]
• Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 9. Vol. 11. 2015b. MIND diet associated with reduced incidence of Alzheimer's disease; pp. 1007–1014. [PMC free article: PMC4532650] [PubMed: 25681666]
• Mortimer JA, Ding D, Borenstein AR, DeCarli C, Guo Q, Wu Y, Zhao Q, Chu S. Journal of Alzheimer's Disease. 4. Vol. 30. 2012. Changes in brain volume and cognition in a randomized trial of exercise and social interaction in a community-based sample of non-demented chinese elders; pp. 757–766. [PMC free article: PMC3788823] [PubMed: 22451320]
• Muldoon MF, Barger SD, Ryan CM, Flory JD, Lehoczky JP, Matthews KA, Manuck SB. American Journal of Medicine. 7. Vol. 108. 2000. Effects of lovastatin on cognitive function and psychological well-being; pp. 538–546. [PubMed: 10806282]
• Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. American Journal of Medicine. 11. Vol. 117. 2004. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults; pp. 823–829. [PubMed: 15589485]
• Mullington JM, Haack M, Toth M, Serrador JM, Meier-Ewert HK. Progress in Cardiovascular Diseases. 4. Vol. 51. 2009. Cardiovascular, inflammatory, and metabolic consequences of sleep deprivation; pp. 294–302. [PMC free article: PMC3403737] [PubMed: 19110131]
• Nahum-Shani I, Smith SN, Spring BJ, Collins LM, Witkiewitz K, Tewari A, Murphy SA. Annals of Behavioral Medicine. 2016. Just-in-Time Adaptive Interventions (JITAIs) in mobile health: Key components and design principles for ongoing health behavior support. doi: https://doi​.org/10.1007​/S12160-016-9830-8. [PMC free article: PMC5364076] [PubMed: 27663578]
• Napoli N, Shah K, Waters DL, Sinacore DR, Qualls C, Villareal DT. American Journal of Clinical Nutrition. 1. Vol. 100. 2014. Effect of weight loss, exercise, or both on cognition and quality of life in obese older adults; pp. 189–198. [PMC free article: PMC4144098] [PubMed: 24787497]
• Nathan DM, Buse JB, Kahn SE, Krause-Steinrauf H, Larkin ME, Staten M, Wexler D, Lachin JM. Diabetes Care. 8. Vol. 36. 2013. Rationale and design of the glycemia reduction approaches in diabetes: A comparative effectiveness study (GRADE) pp. 2254–2261. [PMC free article: PMC3714493] [PubMed: 23690531]
• Navar-Boggan AM, Pencina MJ, Williams K, Sniderman AD, Peterson ED. Journal of the American Medical Association. 14. Vol. 311. 2014. Proportion of U.S. adults potentially affected by the 2014 hypertension guideline; pp. 1424–1429. [PubMed: 24682242]
• Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, Backman L, Hanninen T, Jula A, Laatikainen T, Lindstrom J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M. The Lancet. 9984. Vol. 385. 2015. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controlled trial; pp. 2255–2263. [PubMed: 25771249]
• O'Luanaigh C, O'Connell H, Chin AV, Hamilton F, Coen R, Walsh C, Walsh JB, Caokley D, Cunningham C, Lawlor BA. Aging & Mental Health. 3. Vol. 16. 2012. Loneliness and cognition in older people: The Dublin Healthy Ageing Study; pp. 347–352. [PubMed: 22129350]
• Ontario Health Technology Advisory Committee. Vitamin B12 and cognitive function: OHTAC recommendation. Toronto, Ontario, Canada: Ontario Health Technology Advisory Committee; 2013.
• Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Neurology. 9. Vol. 53. 1999. Diabetes mellitus and the risk of dementia: The Rotterdam Study; pp. 1937–1942. [PubMed: 10599761]
• Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Archives of General Psychiatry. 5. Vol. 63. 2006. Depression and risk for Alzheimer disease: Systematic review, meta-analysis, and metaregression analysis; pp. 530–538. [PMC free article: PMC3530614] [PubMed: 16651510]
• Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, Girones X, Henry TL, Matsubara E, Zambon D, Wolozin B, Sano M, Cruz-Sanchez FF, Thal LJ, Petanceska SS, Refolo LM. Neurology. 2. Vol. 61. 2003. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology; pp. 199–205. [PubMed: 12874399]
• Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, Chang TY, Tanzi RE, Kovacs DM. Nature Cell Biology. 10. Vol. 3. 2001. Acyl-coenzyme A: Cholesterol acyltransferase modulates the generation of the amyloid beta-peptide; pp. 905–912. [PubMed: 11584272]
• Puglielli L, Tanzi RE, Kovacs DM. Nature Neuroscience. 4. Vol. 6. 2003. Alzheimer's disease: The cholesterol connection; pp. 345–351. [PubMed: 12658281]
• Rapp SR, Luchsinger JA, Baker LD, Blackburn GL, Hazuda HP, Demos-McDermott KE, Jeffery RW, Keller JN, McCaffery JM, Pajewski NM, Evans M, Wadden TA, Arnold SE, Espeland MA. Journal of the American Geriatrics Society. 5. Vol. 65. 2017. Effect of a long-term intensive lifestyle intervention on cognitive function: Action for health in diabetes study; pp. 966–972. [PMC free article: PMC5435531] [PubMed: 28067945]
• Raskin J, Wiltse CG, Siegal A, Sheikh J, Xu J, Dinkel JJ, Rotz BT, Mohs RC. American Journal of Psychiatry. 6. Vol. 164. 2007. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: An 8-week, double-blind, placebo-controlled trial; pp. 900–909. [PubMed: 17541049]
• Rawlings AM, Sharrett AR, Schneider AL, Coresh J, Albert M, Couper D, Griswold M, Gottesman RF, Wagenknecht LE, Windham BG, Selvin E. Annals of Internal Medicine. 11. Vol. 161. 2014. Diabetes in midlife and cognitive change over 20 years: A cohort study; pp. 785–793. [PMC free article: PMC4432464] [PubMed: 25437406]
• Santanello NC, Barber BL, Applegate WB, Elam J, Curtis C, Hunninghake DB, Gordon DJ. Journal of the American Geriatrics Society. 1. Vol. 45. 1997. Effect of pharmacologic lipid lowering on health-related quality of life in older persons: Results from the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study; pp. 8–14. [PubMed: 8994481]
• Satizabal CL, Beiser AS, Chouraki V, Chene G, Dufouil C, Seshadri S. New England Journal of Medicine. 6. Vol. 374. 2016. Incidence of dementia over three decades in the Framingham Heart Study; pp. 523–532. [PMC free article: PMC4943081] [PubMed: 26863354]
• Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. Archives of Neurology. 2. Vol. 66. 2009. Mediterranean diet and mild cognitive impairment; pp. 216–225. [PMC free article: PMC2653223] [PubMed: 19204158]
• Schadt EE, Buchanan S, Brennand KJ, Merchant KM. Frontiers in Pharmacology. Vol. 5. 2014. Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders; pp. 1–15. [PMC free article: PMC4251289] [PubMed: 25520658]
• Schneider LS, Sano M. Alzheimer's & Dementia. 5. Vol. 5. 2009. Current Alzheimer's disease clinical trials: Methods and placebo outcomes; pp. 388–397. [PMC free article: PMC3321732] [PubMed: 19751918]
• Seaquist ER, Miller ME, Fonseca V, Ismail-Beigi F, Launer LJ, Punthakee Z, Sood A. Journal of Diabetes & Its Complications. 5. Vol. 27. 2013. Effect of thiazolidinediones and insulin on cognitive outcomes in ACCORD-MIND; pp. 485–491. [PMC free article: PMC3748242] [PubMed: 23680059]
• Shankar A, Hamer M, McMunn A, Steptoe A. Psychosomatic Medicine. 2. Vol. 75. 2013. Social isolation and loneliness: Relationships with cognitive function during 4 years of follow-up in the English Longitudinal Study of Ageing; pp. 161–170. [PubMed: 23362501]
• Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH. Journal of the American Medical Association. 24. Vol. 291. 2004. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study; pp. 2947–2958. [PubMed: 15213206]
• Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Lui-seifert H, Dowsett SA, Pontecorvo MJ, Dean RA, Demattos R. Alzheimer's & Dementia: Journal of the Alzheimer's Association. 2. Vol. 12. 2016. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients; pp. 110–120. [PubMed: 26238576]
• Singh B, Parsaik AK, Mielke MM, Erwin PJ, Knopman DS, Petersen RC, Roberts RO. Journal of Alzheimer's Disease. 2. Vol. 39. 2014. Association of Mediterranean diet with mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis; pp. 271–282. [PMC free article: PMC3946820] [PubMed: 24164735]
• Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H. PLoS ONE. 9. Vol. 5. 2010. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: A randomized controlled trial; p. e12244. [PMC free article: PMC2935890] [PubMed: 20838622]
• Spira AP, Gamaldo AA, An Y, Wu MN, Simonsick EM, Bilgel M, Zhou Y, Wong DF, Ferrucci L, Resnick SM. JAMA Neurology. 12. Vol. 70. 2013. Self-reported sleep and β-amyloid deposition in community-dwelling older adults; pp. 1537–1543. [PMC free article: PMC3918480] [PubMed: 24145859]
• Spira AP, Yager C, Brandt J, Smith GS, Zhou Y, Mathur A, Kumar A, Brasic JR, Wu MN. SAGE Open Medicine. Vol. 2. 2014. Objectively measured sleep and β-amyloid burden in older adults: A pilot study; p. 2050312114546520. [PMC free article: PMC4304392] [PubMed: 25621174]
• The SPRINT Research Group. New England Journal of Medicine. 22. Vol. 373. 2015. A randomized trial of intensive versus standard blood-pressure control; pp. 2103–2116. [PMC free article: PMC4689591] [PubMed: 26551272]
• Steenland K, Zhao L, Goldstein FC, Levey AI. Journal of the American Geriatrics Society. 9. Vol. 61. 2013. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment; pp. 1449–1455. [PMC free article: PMC3773248] [PubMed: 24000778]
• Stine-Morrow EA, Payne BR, Roberts BW, Kramer AF, Morrow DG, Payne L, Hill PL, Jackson JJ, Gao X, Noh SR, Janke MC, Parisi JM. Psychology & Aging. 4. Vol. 29. 2014. Training versus engagement as paths to cognitive enrichment with aging; pp. 891–906. [PMC free article: PMC4361254] [PubMed: 25402337]
• Tangney CC. Current Nutrition Reports. 1. Vol. 3. 2014. DASH and Mediterranean-type dietary patterns to maintain cognitive health; pp. 51–61. [PMC free article: PMC4295785] [PubMed: 25599006]
• Tangney CC, Li H, Wang Y, Barnes L, Schneider JA, Bennett DA, Morris MC. Neurology. 16. Vol. 83. 2014. Relation of DASH- and Mediterranean-like dietary patterns to cognitive decline in older persons; pp. 1410–1416. [PMC free article: PMC4206157] [PubMed: 25230996]
• Tendolkar I, Enajat M, Zwiers MP, van Wingen G, de Leeuw FE, van Kuilenburg J, Bouwels L, Pop G, Pop-Purceleanu M. International Journal of Geriatric Psychiatry. 1. Vol. 27. 2012. One-year cholesterol lowering treatment reduces medial temporal lobe atrophy and memory decline in stroke-free elderly with atrial fibrillation: Evidence from a parallel group randomized trial; pp. 49–58. [PubMed: 21308791]
• Toh BH, van Driel IR, Gleeson PA. New England Journal of Medicine. 20. Vol. 337. 1997. Pernicious anemia; pp. 1441–1448. [PubMed: 9358143]
• Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martinez-Gonzalez MA, Martinez-Lapiscina EH, Fito M, Perez-Heras A, Salas-Salvado J, Estruch R, Ros E. JAMA Internal Medicine. 7. Vol. 175. 2015. Mediterranean diet and age-related cognitive decline: A randomized clinical trial; pp. 1094–1103. [PubMed: 25961184]
• van de Rest O, van der Zwaluw NL, Tieland M, Adam JJ, Hiddink GJ, van Loon LJ, de Groot LC. Mechanisms of Ageing & Development. 136-137. 2014. Effect of resistance-type exercise training with or without protein supplementation on cognitive functioning in frail and pre-frail elderly: Secondary analysis of a randomized, double-blind, placebo-controlled trial; pp. 85–93. [PubMed: 24374288]
• van de Rest O, Berendsen AA, Haveman-Nies A, de Groot LC. Advances in Nutrition: An International Review Journal. 2. Vol. 6. 2015. Dietary patterns, cognitive decline, and dementia: A systematic review; pp. 154–168. [PMC free article: PMC4352174] [PubMed: 25770254]
• van der Zwaluw NL, Dhonukshe-Rutten RA, van Wijngaarden JP, Brouwer-Brolsma EM, van de Rest O, In't Veld PH, Enneman AW, van Dijk SC, Ham AC, Swart KM, van der Velde N, van Schoor NM, van der Cammen TJ, Uitterlinden AG, Lips P, Kessels RP, de Groot LC. Neurology. 23. Vol. 83. 2014a. Results of 2-year vitamin B treatment on cognitive performance: Secondary data from an RCT; pp. 2158–2166. [PubMed: 25391305]
• van der Zwaluw NL, van de Rest O, Tieland M, Adam JJ, Hiddink GJ, van Loon LJ, de Groot LC. European Journal of Nutrition. 3. Vol. 53. 2014b. The impact of protein supplementation on cognitive performance in frail elderly; pp. 803–812. [PubMed: 24045855]
• van Vliet P. Journal of Alzheimer's Disease. Suppl 2. Vol. 30. 2012. Cholesterol and late-life cognitive decline; pp. S147–S162. [PubMed: 22269162]
• Vellas B, Carrie I, Gillette-Guyonnet S, Touchon J, Dantoine T, Dartigues JF, Cuffi MN, Bordes S, Gasnier Y, Robert P, Bories L, Rouaud O, Desclaux F, Sudres K, Bonnefoy M, Pesce A, Dufouil C, Lehericy S, Chupin M, Mangin JF, Payoux P, Adel D, Legrand P, Catheline D, Kanony C, Zaim M, Molinier L, Costa N, Delrieu J, Voisin T, Faisant C, Lala F, Nourhashemi F, Rolland Y, Van Kan GA, Dupuy C, Cantet C, Cestac P, Belleville S, Willis S, Cesari M, Weiner MW, Soto ME, Ousset PJ, Andrieu S. Journal of Prevention of Alzheimer's Disease. 1. Vol. 1. 2014. MAPT Study: A multidomain approach for preventing Alzheimer's disease: Design and baseline data; pp. 13–22. [PMC free article: PMC4652787] [PubMed: 26594639]
• Verghese J. Physical activity and diet. Washington, DC: Oct 25, 2016. Paper presented at Preventing Dementia and Cognitive Impairment: A Workshop.
• Wade AG, Farmer M, Harari G, Fund N, Laudon M, Nir T, Frydman-Marom A, Zisapel N. Journal of Clinical Interventions in Aging. Vol. 9. 2014. Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer's disease: A 6-month, randomized, placebo-controlled, multicenter trial; pp. 947–961. [PMC free article: PMC4069047] [PubMed: 24971004]
• Walker JG, Batterham PJ, Mackinnon AJ, Jorm AF, Hickie I, Fenech M, Kljakovic M, Crisp D, Christensen H. American Journal of Clinical Nutrition. 1. Vol. 95. 2012. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms—the Beyond Ageing Project: A randomized controlled trial; pp. 194–203. [PubMed: 22170358]
• Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Neurology. 2. Vol. 64. 2005. Midlife cardiovascular risk factors and risk of dementia in late life; pp. 277–281. [PubMed: 15668425]
• Wilckens KA, Hall MH, Nebes RD, Monk TH, Buysse DJ. Behavioral Sleep Medicine. 3. Vol. 14. 2016. Changes in cognitive performance are associated with changes in sleep in older adults with insomnia; pp. 295–310. [PMC free article: PMC4775463] [PubMed: 26322904]
• Williamson JD, Launer LJ, Bryan RN, Coker LH, Lazar RM, Gerstein HC, Murray AM, Sullivan MD, Horowitz KR, Ding J, Marcovina S, Lovato L, Lovato J, Margolis KL, Davatzikos C, Barzilay J, Ginsberg HN, Linz PE, Miller ME. JAMA Internal Medicine. 3. Vol. 174. 2014. Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels: A randomized clinical trial; pp. 324–333. [PMC free article: PMC4423790] [PubMed: 24493100]
• Winker MA. Journal of the American Medical Association. 13. Vol. 271. 1994. Tacrine for Alzheimer's disease: Which patient, what dose? pp. 1023–1024. [PubMed: 8139061]
• Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Archives of Neurology. 10. Vol. 57. 2000. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme a reductase inhibitors; pp. 1439–1443. [PubMed: 11030795]
• Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Science. 6156. Vol. 342. 2013. Sleep drives metabolite clearance from the adult brain; pp. 373–377. [PMC free article: PMC3880190] [PubMed: 24136970]
• Yaffe K, Falvey CM, Hoang T. The Lancet Neurology. 10. Vol. 13. 2014. Connections between sleep and cognition in older adults; pp. 1017–1028. [PubMed: 25231524]
• Yang Q, Wang Y, Feng J, Cao J, Chen B. Journal of Neuropsychiatric Disease and Treatment. Vol. 9. 2013. Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: The potential roles played by microglia; pp. 1077–1086. [PMC free article: PMC3742344] [PubMed: 23950649]
• Zamora-Ros R, Serafini M, Estruch R, Lamuela-Raventós RM, Martínez-González MA, Salas-Salvadó J, Fiol M, Lapetra J, Arós F, Covas MI, Andres-Lacueva C. Nutrition, Metabolism and Cardiovascular Diseases. 12. Vol. 23. 2013. Mediterranean diet and non enzymatic antioxidant capacity in the PREDIMED study: Evidence for a mechanism of antioxidant tuning; pp. 1167–1174. [PubMed: 23484910]
• Zisapel N. CNS Drugs. 4. Vol. 15. 2001. Circadian rhythm sleep disorders: Pathophysiology and potential approaches to management; pp. 311–328. [PubMed: 11463135]
• Zissimopoulos JM, Barthold D, Brinton RD, Joyce G. JAMA Neurology. 2. Vol. 74. 2016. Sex and race differences in the association between statin use and the incidence of Alzheimer disease; pp. 225–232. [PMC free article: PMC5646357] [PubMed: 27942728]