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4 Priorities for Future Research
Pages 95-140

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From page 95...
... The committee also identifies other interventions that, based on data from RCTs and observational studies, as well as a strong argument for biological plausibility, appear to be potentially promising and worth prioritizing in future research. In addition, this chapter identifies those specific interventions that the committee believes should be of lowest priority for future research because the AHRQ systematic review found no evidence of any benefit and some low-strength evidence to suggest that these interventions do not prevent cognitive decline or dementia or, in one case, some evidence of increased risk of harm.
From page 96...
... Multimodal Approaches Multimodal interventions utilize a combination of components -- such as physical activity, diet, social engagement, and cognitive training -- that target multiple dementia risk factors simultaneously. Although most available research on preventing cognitive decline and dementia reflects the quest for a single strong solution, multimodal approaches may be more effective than single-component interventions.
From page 97...
... , a large trial of an intervention consisting of physical activity, nutrition counseling, cognitive training, and management of vascular risk factors that was carried out in a population of adults at risk for cardiovascular disease. Although the effect of the intervention on dementia incidence was not measured, the intervention group showed significantly improved cognitive performance after 24 months compared with an attention control group (Ngandu et al., 2015)
From page 98...
... . The pilot study, which was not included in the AHRQ systematic review because of a high risk of bias from attrition, showed that the intervention group demonstrated improved memory and executive function, while declines were observed in a waitlist control group.
From page 99...
... to prevent or delay disease. Adherence One final cross-cutting consideration for future intervention research studies is the challenge of promoting adherence to interventions, as lack of adherence may reduce the observed effect of an intervention on cognitive outcomes.
From page 100...
... . As discussed in Chapter 2, however, the existing body of evidence is limited, and the AHRQ systematic review findings were based primarily on a single large and long-duration study -- the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)
From page 101...
... Blood Pressure Management As described in Chapter 2, the committee emphasizes that further research on the effectiveness of blood pressure management in preventing cognitive decline and dementia is a priority. A definitive answer may never be obtained through RCTs since a placebo-controlled trial may not be considered ethical in a hypertensive population, given the known cardiovascular benefits of blood pressure management.
From page 102...
... ? • Does a focus on blood pressure in isolation from other vascular risk factors limit the impact on cognitive outcomes?
From page 103...
... 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
From page 104...
... . Future Research Questions and Directions Antidementia treatments evaluated in studies included in the AHRQ systematic review were limited to acetylcholinesterase inhibitors, which were assessed for effects on cognitive performance in people with subjective complaints of cognitive loss or diagnosed MCI, and on progression from MCI to CATD.
From page 105...
... , 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)
From page 106...
... .  AHRQ SYSTEMATIC REVIEW: BOX 4-1 SUMMARY OF FINDINGS ON DIABETES MEDICATION TREATMENT •  studies reported on the effect of diabetes treatment on the risk of No incident clinical diagnoses of MCI or CATD.a •  middle-aged older adults with diabetes and presumed normal cogni In tion, low-strength evidence shows intensive versus standard glycemic control had no significant effect on cognitive performance.
From page 107...
... . 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)
From page 108...
... 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.
From page 109...
... 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 Asso ciation prevent cognitive decline among people with diabetes?
From page 110...
... , 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  BOX 4-2 AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON DEPRESSION INTERVENTIONS No relevant studies for depression treatments were found.
From page 111...
... 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 4  Consistent with the AHRQ systematic review, vitamins were considered separately from dietary interventions for the purposes of this report, and certain specific vitamins are addressed elsewhere in this chapter.
From page 112...
... . Specific diets found in these studies to be associated with improved cognitive function or reduced  BOX 4-3 AHRQ SYSTEMATIC REVIEW: SUMMARY OF FINDINGS ON DIET INTERVENTIONS E  vidence is insufficient to conclude whether protein supplementation or energy-deficit diets have an effect on cognitive performance or incidence of MCI or CATD.
From page 113...
... . However, these studies were considered to be at high risk of bias because of high ­evels of l attrition, and therefore were not considered in the AHRQ systematic review.
From page 114...
... 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)
From page 115...
... 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.
From page 116...
... . 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.
From page 117...
... . Supplemental Information and Considerations Although the AHRQ systematic review did not find sufficient evidence to indicate whether sleep interventions can prevent cognitive decline and  AHRQ SYSTEMATIC REVIEW: BOX 4-5 SUMMARY OF FINDINGS ON SLEEP QUALITY INTERVENTIONS Evidence was insufficient for sleep interventions.
From page 118...
... 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)
From page 119...
... 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.
From page 120...
... . 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?
From page 121...
... 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)
From page 122...
... 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.
From page 123...
... SOURCE: Kane et al., 2017. AHRQ systematic review because of their observed detrimental effects on cognition in women aged 65 or older (as summarized in Box 4-8)
From page 124...
... 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.
From page 125...
... aPlease see general discussion of antidementia drugs in previous section. bThe committee believes that the randomized controlled trial data suggesting lack of benefit from omega-3 fatty acid supplementation is weak and counterbalanced by encouraging evidence from observational studies and preliminary results from ongo ing studies such as the Multidomain Alzheimer's Prevention Trial (MAPT)
From page 126...
... Some large studies already under way may help address these questions. Recommendation 3: Highest Priorities for Research The National Institutes of Health and other interested organiza tions should support further research to strengthen the evidence base on the following categories of interventions, alone or in com bination, which are supported by encouraging but inconclusive evidence: • cognitive training • blood pressure management • increased physical activity CONCLUSION: There is insufficient evidence with which to assess the effectiveness of the following interventions in preventing cogni tive decline and dementia: diabetes treatment, dietary interventions, depression treatment, lipid-lowering treatment, sleep quality inter ventions, social engagement interventions, and vitamin B12 plus folic 6  Only three cholinesterase inhibitors are commonly used to treat dementia symptoms, as one -- tacrine -- has been associated with toxicity and significant adverse effects (Winker, 1994)
From page 127...
... Recommendation 4: Additional Priorities for Research The National Institutes of Health and other interested organiza tions should support research to strengthen the evidence base on the following categories of interventions, alone or in combination, for which there is currently insufficient evidence to determine their effectiveness: • new antidementia treatments that can delay onset or slow disease progression • diabetes treatment • depression treatment • dietary interventions • lipid-lowering treatment/statins • sleep quality interventions • social engagement interventions • vitamin B12 plus folic acid supplementation 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.
From page 128...
... 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.
From page 129...
... trial: A randomized controlled trial to enhance cognitive function in older adults. JAMA Internal Medicine 173(9)
From page 130...
... 2015. Progress in the TOMMORROW Study: A phar macogenetics supported clinical trial to delay onset of mild cognitive impairment due to Alzheimer's disease with low-dose pioglitazone.
From page 131...
... 2011. Mild cognitive impairment and de mentia: The importance of modifiable risk factors.
From page 132...
... Cochrane Database of Systematic Reviews 2:CD003946. Gerstein, H
From page 133...
... 2017. Interventions to prevent age-related cognitive decline, mild cognitive impairment, and clinical Alzheimer's-type dementia.
From page 134...
... 2007. Examination of cognitive function during six months of calorie restric tion: Results of a randomized controlled trial.
From page 135...
... 2015. A 2 year multidomain intervention of diet, exer cise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER)
From page 136...
... 2006. Depression and risk for Alzheimer disease: Systematic review, meta-analysis, and metaregression analysis.
From page 137...
... 2014. Association of Mediterranean diet with mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis.
From page 138...
... 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.
From page 139...
... 2013. Mediterranean diet and non enzymatic antioxidant capacity in the PREDIMED study: Evidence for a mechanism of antioxidant tuning.


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