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CCCDTD5: Reducing the risk of later‐life dementia. Evidence informing the Fifth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD‐5)

Abstract The Fifth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD‐5) was a year‐long process to synthesize the best available evidence on several topics. Our group undertook evaluation of risk reduction, in eight domains: nutrition; physical activity; hearing; sleep; cognitive training and stimulation; social engagement and education; frailty; and medications. Here we describe the rationale for the undertaking and summarize the background evidence—this is also tabulated in the Appendix. We further comment specifically on the relationship between age and dementia, and offer some suggestions for how reducing the risk of dementia in the seventh decade and beyond might be considered if we are to improve prospects for prevention in the near term. We draw to attention that a well‐specified model of success in dementia prevention need not equate to the elimination of cognitive impairment in late life.

Dementia prevention increasingly seems plausible. 1,2 In many countries the age-adjusted incidence of dementia is falling, and although the meanings, mechanisms, and extent are contested, a lower incidence challenges the dogma of dementia as inevitable. 3,4 Internationally two streams of dementia prevention efforts are recognized. One is multidomain "lifestyle" interventions, catalyzed by the Finnish GHeriatric Intervnetion Study to Prevent Cogbnitve Imapirment and Disabikity (FINGER) trial's demonstration that some individuals benefit (albeit with considerable effort) 5 . Its promise is being tested on a large scale 6 including a plan to build on the pan-Canadian COMPrehensive ASSessment of Neurodegeneration and Dementia (COMPASS-ND) study. 7 Skepticism abounds, especially whether such lifestyle interventions can ever be effective in people possessing an apolipoprotein E (APOE) ε4 allele. Both sides of the argument can muster evidence in their favor. [8][9][10] The second prevention approach also comes with controversy: It is the effort to intervene on the mechanism(s) said to give rise to Alzheimer's disease (AD). For now, this mostly consists in seeing the disease as one or a series of single-protein abnormalities. The antiamyloid monoclonal antibody medication aducanumab showed initial promise, 11 and although it was judged likely to be futile to continue testing 12 most recently the drug been resurrected. 13 This has not been without controversy. 13,14 This and like efforts represent one approach, and one that is commanding substantial resources.
The reason to consider other approaches is that most dementia occurs in late life-in Canada most cases occur between the ages of 75 and 95. 15 Most people with dementia by that age are frail to some degree. 16 The degree of frailty is important both in the risk for late-life cognitive impairment 17 and in whether people with the neuropathological features of AD (diffuse and neuritic plaques, and neurofibrillary tangles) are expressed as clinical dementia. 18 In consequence, there remains merit in exploring ways to prevent dementia that focus on putatively proximal causes and to consider how overall health affects brain health. Furthermore, and especially in low and middle-income countries, whatever interventions are undertaken should be cost-effective enough, and priced so as to be widely available. 3 Against this background, the Fifth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD-5) took a broad view of late-life dementia. 19 We reflected on the fact not just that most dementia occurs in late life but that it is believed to have multiple causes. The community-based Rush studies suggest that although the risk of dementia attributed to AD is about 65%, this is the case only when combined with seven other neuropathological features. 20 AD exists on its own in only 9% of cases at autopsy. 21 For the most part, we were able to build updates from a 2017 comprehensive overview of dementia prevention. 1 In each case of new methods and targets, however, we supplemented information there (when present) with updates, especially focusing on Canadian data. In consequence, we offer recommendations on nutrition, physical exercise, hearing loss, sleep, cognitive training and rehabilitation, social deprivation, frailty, and anticholinergic medications; vascular risk factors were the focus of a separate inquiry. These many interventions appear to have importance both across the life course and in primary, secondary, and sometimes tertiary AD prevention.

METHODS
As outlined in the main paper, 19  To increase the chance of applicability to practice context (an AGREE II rating criterion) we also sought out Canadian data when available and relevant. Here we recapitulate the recommendations from the main paper 19 and describe the items that did not meet the required 80% threshold. For each recommendation, we offer a short narrative summary. The key evidence is summarized in tables, presented in an Appendix.

Nutrition
Overall, against the background of ambient risk from a regular diet, some dietary factors appear to either increase the risk of cognitive decline or to protect against it. Risk is conferred by diets high in alcohol, saturated fats, and refined sugars (Appendix; Table 1).
Recommendation 1a and allow consumption of saturated fatty acids (SFAs) to reduce the risk of cognitive decline. GRADE 1B (92%).
1c. We recommend increasing fruit and vegetable intake.

Physical activity
Recommendations 2-4 (Box 2). The data on physical exercise continue to evolve. As is not rare, going from observational studies to clinical trials is accompanied by a diminution in the size of treatment effects, but still suggest benefit. The controlled trials evidence is also remarkable for some heterogeneity in impact based on the type of exercise and its intensity.
We recommend physical activity interventions to improve cognitive outcomes among older adults, including those with MCI. [33][34][35][36][37][38] Evidence supports that both aerobic and resistance exercise have the potential to improve cognitive outcomes, which supports the notion that a multimodal exercise program might lead to larger gain.
However, comparative studies of multi-modal versus aerobic exercise a. We recommend aerobic exercise and/or resistance training of at least moderate intensity to improve cognitive outcomes among older adults. GRADE 1B (94%).
b. There is promising evidence that dance interventions and mind-body exercise (for example, tai chi, qi gong) of moderate dose improve cognitive outcomes among older adults but results from larger, high-quality trials are needed. GRADE 2B (84%).

We recommend physical activity interventions to
improve cognitive outcomes among people with mild cognitive impairment (MCI). GRADE 2B (94%).
a. We recommend aerobic exercise to improve cognitive outcomes among people with MCI. Grade 2B (94%).
b. There is promising evidence to support resistance training and mind-body exercise (eg, tai chi, qi gong) to improve cognitive outcomes among older adults with MCI but results from larger, high-quality trials are needed. Grade 2C (83%).

We recommend physical activity interventions to reduce
the risk of dementia, including AD and vascular dementia.

GRADE 2B. (96%).
or resistance training only are not yet available. There is also emerging evidence that other forms of exercise such as dance and mind-body exercise (eg, tai chi, qi gong) may improve cognitive outcomes among older adults, though the type of mind-body exercise may again moderate effects. [34][35][36]38 While improving cognitive outcomes in both healthy adults and those with MCI might reasonably lead to an effective reduction of dementia, direct evidence from clinical trials that physical activity interventions reduce the risk of dementia is still lacking. 39 Despite this gap, the pattern of results across several earlier observational studies and randomized controlled trials (RCTs) among adults with and without MCI provides support to recommend physical activity interventions as a part of dementia prevention strategies 40 (Appendix; Table   2). In addition, physical activity is understood to improve cardiovascular and cerebrovascular health, which may contribute to dementia risk 41 (Appendix; after the active intervention period. Some may benefit from passive monitoring of the quality of the exercise (eg, via apps). In addition, the evidence is still inconclusive regarding effects to brain structure; this requires more high quality, large trials with imaging. 44 Exercise is likely appropriate "pre-hab" even in cases where people require interventions that might increase the risk of delirium (eg, surgery, chemotherapy). 42,[45][46][47][48] There is a need to individualize exercise recommendations, including tailoring for adherence and behavior change, both when recommending exercise and when designing long-term interventions. Potential differences between women/men require further evaluation. 49

Sleep
Recommendation 7a BOX 4 (sleep apnea). A body of large observational studies in diverse populations of older adults supports an association between sleep apnea, incident cognitive decline and dementia, and biomarkers of AD pathology 62-65 (Appendix;

Social engagement and education
Recommendation 9a BOX 6 (Social context and attention to social circumstances across the life course). Intervention studies are limited, although it is interesting to note that social interaction has (explicitly or implicitly) been part of multimodal intervention studies and may be a component of other interventions that appear to be unidimensional (eg, group exercise classes or cognitive training 1,33-37 (Appendix; Table 6, Recommendations 9 a and b).
Recommendation 9a BOX 6 (Special importance of educational attainment in early life). Low educational attainment as a dementia risk has been consistently well established in observational studies (Appendix; Table 6, Recommendations 9 a and b). Education has also been proposed as a key contributor to cognitive reserve. 100 The contribution of bilingualism to cognitive reserve has also been studied, although associations have been less clear in prospective studies, and observational studies are prone to confounding by education and cultural differences. 101 The timing of educational experience is relevant to consider, and it is unclear how the (clearly demonstrated) benefits of

Frailty
Frailty defined either as a specific phenotype 102 or as a state 103 has been linked to cognitive decline in both communitybased observational studies and in relation to biomarkers and neuropathology. 17,104,105 It also mediates the relationship between neuropathology and cognitive impairment, such that people with a low degree of frailty and a low degree of neuropathology are least likely to express dementia, whereas those with high degrees of each frailty and neuropathology are most likely to express dementia. 18 Given their shared risk factors-including a strong relationship to ageing-there is overlap between interventions, such as exercise 106 (Appendix; Table 7, Recommendation 10). The term "cognitive frailty" has been proposed to capture the co-occurrence of MCI and the physical frailty phenotype; its status as an entity is controversial and is not basis for the current recommendation. 107

CONCLUSIONS
The prevention group has made specific recommendations to suggest that people at risk of dementia be encouraged to adhere to a balanced Finally a key point in understanding the impact of a preventive maneuver is to understand what success might look like. A model of success that obliges a diagnosis of "no cognitive impairment" as the outcome is highly likely to disappoint. This may be especially true, for competing reasons, for diagnoses that rely on a biomarker-defined disease, instead of clinically defined understanding of the degree of cognitive, functional, and behavioral impairment. Given the well-known poor correlation between the degree of neuropathology and the degree of cognitive impairment-and that this relationship is moderated by the overall health of the individual 18 -imagining that success should entail change biomarker levels may be impose on the biomarkers a burden that they cannot bear. What is important to people living with dementia, and to their caretakers, may not readily conform to a model of disease reversal: Individually meaningful success can be achieved short of cure. [130][131][132] Similarly, patient and caregiver reports of how late-life cognitive impairment impacts on their preferences and life satisfaction may also offer insights into just what successful prevention might consist. None of the other co-authors have conflicts of interest to declare.