This section provides an overview of each PICO question described under the following headings: background; recommendations and additional considerations; supporting evidence for the recommendations and the rationale for the recommendations based on the evidence synthesized as well as criteria listed in the EtD tables. Complete evidence profiles for each PICO question including the GRADE tables and the EtD tables are included in the Web Annex.
3.1. Physical Activity Interventions
For adults with normal cognition or MCI, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults (age above 18 years) with normal cognition or MCI
Intervention:
Physical activity interventions (aerobic, resistance training or multicomponent physical activity)
Comparison:
Care as usual or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
A physically active lifestyle is linked to brain health. In large observational studies with follow-up periods extending decades, physically active people seem less likely to develop cognitive decline, all-cause dementia, vascular dementia and Alzheimer disease when compared with inactive people (Gallaway et al., 2017; Hamer & Chida, 2009; Sofi et al., 2011; Stephen et al., 2017). Especially, the highest levels of physical exercise seem to be most protective (Hamer & Chida, 2009; Sofi et al., 2011). Physical activity seems to have beneficial effects on brain structures, which may underlie this association (Rovio et al., 2010).
Other potential mechanisms underlying the association are most likely indirect, such as the positive effects of physical exercise on other modifiable cardiovascular risk factors (CVRFs), including hypertension, insulin resistance and high cholesterol levels as well as other biological mechanisms, including but not limited to enhancing the immune system function, anti-inflammatory properties, and increasing neurotrophic factors. Physical activity interventions are described in WHO’s Global recommendations on physical activity for health (2010).
Recommendations and Considerations
Recommendation 1
Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline.
Quality of evidence: moderate
Strength of the recommendation: strong
Recommendation 2
Physical activity may be recommended to adults with MCI to reduce the risk of cognitive decline.
Quality of evidence: low
Strength of the recommendation: conditional
WHO’s Global recommendations on physical activity for health (2010)
Below is an extract from these recommendations for adults 65 years and above:
For adults 65 years and above, physical activity includes recreational or leisure-time physical activity, transportation (e.g. walking or cycling), occupational (if the person is still engaged in work), household chores, play, games, sports or planned exercise, in the context of daily, family, and community activities. In order to improve cardiorespiratory and muscular fitness, bone and functional health, and reduce the risk of NCDs, depression and cognitive decline, the following are recommended:
Adults aged 65 years and above should do at least 150 minutes of moderate-intensity aerobic physical activity throughout the week, or do at least 75 minutes of vigorous-intensity aerobic physical activity throughout the week, or an equivalent combination of moderate- and vigorous-intensity activity.
Aerobic activity should be performed in bouts of at least 10 minutes’ duration.
For additional health benefits, adults aged 65 years and above should increase their moderate-intensity aerobic physical activity to 300 minutes per week, or engage in 150 minutes of vigorous-intensity aerobic physical activity per week, or an equivalent combination of moderate-and vigorous-intensity activity.
Adults of this age group with poor mobility should perform physical activity to enhance balance and prevent falls on 3 or more days per week.
Muscle-strengthening activities should be done involving major muscle groups, on 2 or more days per week.
When adults of this age group cannot do the recommended amounts of physical activity due to health conditions, they should be as physically active as their abilities and conditions allow.
Overall, across all the age groups, the benefits of implementing the above recommendations, and of being physically active, outweigh the harms. At the recommended level of 150 minutes per week of moderate-intensity activity, musculoskeletal injury rates appear to be uncommon. In a population-based approach, in order to decrease the risks of musculoskeletal injuries, it would be appropriate to encourage a moderate start with gradual progress to higher levels of physical activity.
Additional considerations include:
Supporting Evidence and Rationale
For physical activity interventions (e.g. aerobic, resistance training or multicomponent physical activity) compared with usual care or no intervention, four systematic reviews were identified for six different physical activity interventions (Barha et al., 2017; Barreto et al., 2017; Northey et al., 2018; Song et al., 2018). These were:
Aerobic exercise intervention versus usual care or no intervention in adults with normal cognition.
Training exercise intervention versus usual care or no intervention in adults with normal cognition.
Multimodal exercise intervention versus usual care or no intervention in adults with normal cognition.
Aerobic exercise intervention versus usual care or no intervention in adults with MCI.
Training exercise intervention versus usual care or no intervention in adults with MCI.
Multimodal exercise intervention versus usual care or no intervention in adults with MCI.
For cognitive outcomes in healthy adults, there is moderate quality evidence which indicates that physical activity interventions have a positive effect on cognition. There is low to moderate quality evidence that suggests that physical activity does not affect risk of MCI and dementia. For cognitive outcomes in adults with MCI, there is low quality evidence that indicates that physical activity interventions have a positive effect on cognition. However, these benefits are not consistent across all cognitive domains.
The evidence shows that the effect size is larger for aerobic training versus resistance training and there is stronger evidence for adults with normal cognition (especially aerobic training) than in adults with MCI.
The GDG concluded that the desirable effects of physical activity outweighed the undesirable effects. Overall, low to moderate quality evidence has shown that physical activity has a small but beneficial effect on cognition. Even in MCI populations, low quality evidence suggests cognitive benefits of physical exercise. The effect of these interventions seems to be mostly due to aerobic exercise. Based on the quality of evidence, a strong recommendation was made for healthy adults and a conditional one for adults with MCI.
3.2. Tobacco Cessation Interventions
For adults with normal cognition or MCI who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI who use tobacco
Intervention:
Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline)
Comparison:
Care as usual or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
Tobacco dependence is the leading cause of preventable death globally, causing an estimated 5 million deaths per year (WHO, 2011) and worldwide medical costs ranging in billions of US dollars (Lightwood et al., 2000). Tobacco is the major risk factor for a number of conditions, including many types of cancers, cardiovascular diseases (CVDs) and risk factors, and respiratory disorders (US Department of Health Human Services, 2004), and tobacco cessation has been demonstrated to significantly reduce these health risks (Pirie et al., 2013). Tobacco cessation has also been associated with reduced depression, anxiety and stress, and improved mood and quality of life compared with continuing to smoke (Taylor et al., 2014).
Tobacco dependence is also associated with other disorders and age-related conditions, such as frailty and work ability in older people (Amorim et al., 2014; Kojima et al., 2015), as well as dementia and cognitive decline (Durazzo et al., 2014).
Interventions to treat tobacco dependence can be very diverse, based on either or both behavioural/psychological strategies and various pharmacological treatments. Non-pharmacological interventions can have mixed results (Niaura, 2008). Counselling is the most frequently used approach, but others have also been explored, such as mindfulness-based approaches, cognitive behavioural therapy, behavioural activation therapy, motivational interviewing, contingency management, and exposure and/or aversion to smoking. Among the pharmacological therapies for tobacco cessation, nicotine replacement therapy, bupropion and varenicline are the most common, but low overall treatment efficacy and adverse effects are key limitations (Gómez-Coronado et al., 2018). Combinations of non-pharmacological and pharmacological approaches seem to be the most effective in supporting tobacco cessation (Gómez-Coronado et al., 2018).
Recommendations and Considerations
Recommendation
Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits.
Quality of evidence: low
Strength of recommendation: strong
Additional considerations include:
Supporting Evidence and Rationale
No systematic reviews comparing tobacco cessation interventions with no intervention were identified.
A large body of observational evidence is available on tobacco smoking as a risk factor for cognitive impairment and dementia. These studies show an association between tobacco smoking (including in mid-life) and dementia, or cognitive decline, in later life (Beydoun et al., 2014; Di Marco et al., 2014; Lafortune et al., 2016; North et al., 2015; Xu et al., 2015; Zhong et al., 2015). Only limited adverse events have been reported and only for pharmacological interventions (Motooka et al., 2018). Therefore, any type of intervention aimed at tobacco cessation is likely to be more beneficial than detrimental.
The GDG made a strong recommendation although evidence from experimental intervention trials is not available, since tobacco use has substantial established harm and the epidemiological/observational evidence on tobacco use and increased risk of dementia fulfils most of the Bradford-Hill’s criteria for causation (Lafortune et al., 2016). The evidence is strong, the population attributable risk is high, reproducible in different settings and with different study designs, specific, and indicates a dose-response effect. In addition, criteria such as temporality (mid-life smoking is correlated to a higher risk of late life dementia) (Lafortune et al., 2016), coherence (experimental laboratory results are in keeping with the observational evidence) (Durazzo et al., 2014) and mechanistic evidence suggest that smoking causes brain damage, underpinning subsequent cognitive decline.
3.3. Nutritional Interventions
3.3a
For adults with normal cognition or MCI, are nutritional interventions including dietary supplements more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI
Intervention:
Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo)
Comparison:
Care as usual/placebo or one treatment versus another
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
3.3b
For adults with normal cognition or MCI, are nutritional interventions such as healthy dietary patterns (e.g. the Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI
Intervention:
Healthy dietary pattern (e.g. the Mediterranean diet)
Comparison:
Care as usual or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
A healthy diet throughout the life course plays a crucial role in optimal development, and in maintaining health and preventing NCDs. Previous dietary intervention studies have shown that dietary changes are involved in prevention of many conditions that increase the risk of dementia, such as diabetes (Diabetes Prevention Program Research Group, 2002; Tuomilehto et al., 2001) and CVD (Rees et al., 2013). Mechanistic and animal models have suggested a variety of pathways that link dietary factors to neuropathological changes in the development of dementia (Swaminathan & Jicha, 2014). Therefore, dietary factors may be involved in the development of dementia, both directly and through their role on other risk factors, and a healthy diet may have a great preventive potential for cognitive impairment.
The Mediterranean diet is the most extensively studied dietary approach, in general as well as in relation to cognitive function. Several systematic reviews of observational studies have concluded that high adherence to the Mediterranean diet is associated with decreased risk of MCI and AD, but modest adherence is not (Singh et al., 2014; Wu & Sun, 2017). Moreover, among participants with normal cognition, higher adherence is associated with better episodic memory and global cognition (Loughrey et al., 2017). Other promising dietary approaches associated with better cognitive function include: dietary approaches to stop hypertension (DASH) (Berendsen et al., 2017; Morris et al., 2015a; 2015b; Wengreen et al., 2013); and the brain health-specific Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet.
Concerning individual foods and nutrients, consumption of fruit and vegetables (Jiang et al., 2017; Wu et al., 2017) and fish (Bakre et al., 2018; Zhang et al., 2016) are most consistently associated with decreased risk of dementia. Higher fish consumption has been linked to lower memory decline among healthy participants in many studies (Samieri et al., 2018), as well as intake of polyunsaturated fatty acids (PUFA) (fish-derived) (Zhang et al., 2016). Other foods and nutrients that have been associated with reduced risk of dementia or cognitive impairment are nuts, olive oil and coffee (Solfrizzi et al., 2017). Evidence has also been reported concerning folate, vitamin E, carotenes, vitamin C and vitamin D (Balion et al., 2012; Dangour et al., 2010; Rafnsson et al., 2013; Travica et al., 2017), but findings are inconsistent.
Recommendations and Considerations
Recommendation 1
The Mediterranean-like diet may be recommended to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia.
Quality of evidence: moderate
Strength of the recommendation: conditional
Recommendation 2
Healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet.
Quality of evidence: low to high (for different dietary components)
Strength of the recommendation: strong
Recommendation 3
Vitamins B and E, PUFA and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia.
Quality of evidence: moderate
Strength of the recommendation: strong
WHO recommendations on a healthy diet
For adults, the WHO guidelines recommend the following.
A healthy diet contains
Fruits, vegetables, legumes (e.g. lentils, beans), nuts and whole grains (e.g. unprocessed maize, millet, oats, wheat, brown rice).
At least 400 g (five portions) of fruits and vegetables a day. Potatoes, sweet potatoes, cassava and other starchy roots are not classified as fruits or vegetables.
Less than 10% of total energy intake from free sugars which is equivalent to 50 g (or around 12 level teaspoons) for a person of healthy body weight consuming approximately 2000 calories per day, but ideally less than 5% of total energy intake for additional health benefits. Most free sugars are added to foods or drinks by the manufacturer, cook or consumer, and can also be found in sugars naturally present in honey, syrups, fruit juices and fruit juice concentrates.
Less than 30% of total energy intake from fats. Unsaturated fats (found in fish, avocado, nuts, sunflower, canola and olive oils) are preferable to saturated fats (found in fatty meat, butter, palm and coconut oil, cream, cheese, ghee and lard) and trans-fats of all kinds, including both industrially produced trans-fats (found in processed food, fast food, snack food, fried food, frozen pizza, pies, cookies, biscuits, wafers, margarines and spreads) and ruminant trans-fats (found in meat and dairy foods from ruminant animals, such as cows, sheep, goats, camels and others). It is suggested to reduce the intake of saturated fats to less than 10% of total energy intake and trans-fats to less than 1% of total energy intake. In particular, industrially produced trans-fats are not part of a healthy diet and should be avoided.
Less than 5 g of salt (equivalent to approximately 1 teaspoon) per day and use iodized salt.
Additional considerations include:
The evidence and recommendations provided assume that the nutritional status and potential micronutrients deficiencies in both mid-life and old age have been assessed and treated.
A balanced and varied diet represents a natural source of polyphenols and protein.
The recommendation about vitamins B and E, PUFA and multi-complex supplementation applies to people without nutrient deficiency.
Supporting Evidence and Rationale
Observational studies have consistently reported that a healthy diet is associated with better cognitive performance (Berendsen et al., 2017; Frith et al., 2018; Loughrey et al., 2017; Morris et al., 2015; Wengreen et al., 2013), but the evidence from clinical trials is more inconsistent (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015a; 2015b; Forbes et al., 2015; Radd-Vagenas et al., 2018; Solfrizzi et al., 2018). It is important to acknowledge that interventions with dietary modifications that improve several aspects of dietary intake at once are more likely to promote better cognition compared with supplementation with only some nutrients. Dietary factors may have synergistic effects that are only evident in combinations of foods (Jacobs Jr et al., 2009).
Regarding nutritional interventions, such as dietary supplements or healthy dietary patterns (e.g. the Mediterranean diet) compared with usual care or no intervention, six systematic reviews were identified for nine different nutritional interventions. These interventions were:
Chicken essence versus placebo (Teoh et al., 2016).
The outcomes of incident MCI and dementia were only reported for interventions involving multi-supplement complexes in adults with normal cognition and the Mediterranean diet (D’Cunha et al., 2018; Radd-Vagenas et al., 2018). However, neither of these interventions showed a direct effect in reducing the incidence of dementia and/or MCI.
All of the interventions/comparisons reported cognitive outcomes. There was moderate quality evidence that the Mediterranean diet can improve verbal and visual memory (Radd-Vagenas et al., 2018). A meta-analysis showed results that approached significance for global cognition and consistently positive, but non-significant, results were reported for all other cognitive outcomes (attention, working memory, processing speed, language and executive function) (Radd-Vagenas et al., 2018). A consistent positive effect of polyphenols on cognitive performance was also found, however, the quality of the evidence was low (Solfrizzi et al., 2018). Similarly, protein supplementations were found to have a beneficial effect on cognition in older adults, but the results were inconsistent and the quality of the evidence was low (Solfrizzi et al., 2018).
Overall, no effects were found for multi-complex (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015), vitamins B and E (Forbes et al., 2015), and PUFA supplementation (Forbes et al., 2015). Low-quality evidence was reported for protein and polyphenols supplementation (Solfrizzi et al., 2018), and moderate evidence of a beneficial effect of the Mediterranean diet was found (Radd-Vagenas et al., 2018).
Three multi-supplement complex interventions: docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) + vitamin E + soy phospholipids + tryptophan + melatonin; vitamin E + multivitamin; lyophilized royal jelly + gingko biloba + Panax ginseng; were examined and none showed an increased risk of any serious adverse event during the follow-up period (moderate quality evidence, Fitzpatrick-Lewis et al., 2015).
The GDG concluded that the benefits of a Mediterranean diet and a balanced diet outweighed the harms and provided conditional and strong recommendations respectively. The GDG noted that vitamin E and protein supplementation at high doses have been associated with undesirable non-anticipated effects that outweigh the benefits and recommended against their use.
3.4. Interventions for Alcohol Use Disorders
For adults with normal cognition or MCI and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI and excessive use of alcohol
Intervention:
Comparison:
Care as usual or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
Excessive alcohol consumption is common in many countries (Gell et al., 2015). In 2012, 5.9% of all deaths worldwide (about 3.3 million) were directly attributable to harmful use of alcohol (WHO, 2014). Furthermore, excessive consumption of alcohol is one of the leading causes of general disability globally (WHO, 2014), being a direct cause in more than 200 diseases including risk factors for dementia and injury conditions (WHO, 1992; WHO 2019a).
There is extensive evidence on excessive alcohol as a risk factor for dementia and cognitive decline (Langballe et al., 2015; Sachdeva et al., 2016; Zhou et al., 2014).
Several approaches have been applied in interventions aimed at hazardous and harmful use of alcohol. Pharmacological therapies with different types of drugs (e.g. opioid antagonists, ALDH2 inhibitors) have shown various degrees of efficacy for adults with alcohol use disorders, although none of them showed to be superior in comparison trials. Behaviour and psychological interventions have shown to be effective in alcohol use disorders, and especially among those with hazardous and harmful drinking. Screening and brief intervention in primary care is one of the most cost-effective means of reducing alcohol-attributable morbidity and deaths (Kaner, 2018). Interventions for alcohol use disorders have been described in the mhGAP Intervention guide - Version 2.0 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/).
Recommendations and Considerations
Recommendation
Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia in addition to other health benefits.
Quality of evidence: moderate (for observational evidence)
Strength of the recommendation: conditional
WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings
The WHO mhGAP Intervention guide recommends the following:
Harmful use of alcohol
Provide psychoeducation and emphasize that the level/pattern of alcohol use is causing harm to health.
Explore the person’s motivations for alcohol use. Conduct motivational interviewing.
Advise stopping alcohol completely or consuming at a non-harmful level (if a non-harmful level exists) and indicate your intention in supporting the person in doing so. Ask the person if they are ready to try to make this change.
Explore strategies for reducing or stopping use and strategies for reducing harm.
Address food, housing and employment needs.
Offer regular follow-up.
Alcohol dependence
Thiamine during alcohol use.
Diazepam during alcohol detoxification to treat withdrawal symptoms.
Naltrexone, acamprosate or disulfiram to prevent relapse after detoxification.
Psychosocial interventions if available, e.g. cognitive behaviour therapy, motivational enhancement therapy, contingency management therapy, family counselling or therapy, problem-solving counselling or therapy; self-help groups.
Additional considerations include:
Interventions can be based on lifestyle/behavioural changes or pharmacological treatments in accordance with the WHO mhGAP guidelines. Lifestyle behavioural interventions are likely to be more acceptable and have fewer adverse events.
A U-shaped relationship between alcohol consumption and cognitive function has been reported. However, due to methodological limitations in most studies that describe this effect, it is not possible to assume that a light to moderate consumption of alcohol is, in fact, protective toward dementia and/or cognitive decline. This, in addition to other health risks and the social and economic burden associated with alcohol, do not favour a general recommendation of its use.
Individual level interventions should be provided in the context of WHO Global strategy to reduce harmful use of alcohol (
WHO 2010) and population level interventions, through strengthening restrictions on alcohol availability, enforcing drink driving countermeasures, facilitating access to screening, brief interventions, and treatment, enforcing bans or comprehensive restrictions on alcohol advertising, sponsorship, and promotion, raising prices on alcohol through excise taxes and pricing policies.
Supporting Evidence and Rationale
No systematic reviews were identified for interventions for hazardous and harmful alcohol consumption (behavioural, psychological and pharmacological interventions) and reduced the risk of cognitive decline and/or dementia.
However, a large body of observational evidence is available on alcohol as a risk factor for cognitive decline and dementia (Beydoun et al., 2014; Hersi et al., 2017; Ilomaki et al., 2015; Lafortune et al., 2016; Piazza-Gardner et al., 2013; Xu et al., 2017). Generally, single studies did not always show similar results (mostly due to differences in study design) but the most consistent pattern is that of a U-shaped relationship between alcohol consumption and dementia and/or cognitive impairment, which clearly links excessive alcohol consumption to a significantly increased risk (Xu et al., 2017).
A range of adverse events has also been reported for pharmacological interventions aimed at reducing excessive alcohol consumption while lifestyle interventions are mostly based on behavioural interventions and no evidence of adverse events (apart from those related to withdrawal syndrome) have been identified (NICE, 2011).
Overall, the GDG concluded that the benefits outweighed the harms and, based on the strong observational evidence, made a conditional recommendation for interventions to reduce or cease hazardous and harmful alcohol use.
3.5. Cognitive Interventions
For adults with normal cognition or MCI is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI
Intervention:
Cognitive stimulation
Cognitive training
Comparison:
Care as usual or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
Dementia is preceded by cognitive decline. However, not everyone who is exposed to dementia risk factors will go on to develop cognitive impairment. The concept of cognitive reserve has been proposed as a protective factor that may reduce the risk of clinical onset of dementia and cognitive decline (Stern, 2012). Cognitive reserve refers to the brain’s ability to cope with or compensate for neuropathology or damage (Stern, 2012). Studies have shown that increased cognitive activity may stimulate (or increase) cognitive reserve and have a buffering effect against rapid cognitive decline (Stern & Munn, 2010) as well as a significant reduction in the risk of MCI or AD diagnosis in those who reported high compared with low levels of cognitive activities (combined OR = 0.38, 95% CI: 0.15–0.99) (Sattler, 2012).
Increased cognitive activity can be achieved through cognitive stimulation therapy and/or cognitive training. Cognitive stimulation therapy refers to “participation in a range of activities aimed at improving cognitive and social functioning” (Clare & Woods, 2004), while cognitive training refers to “guided practice of specific standardized tasks designed to enhance particular cognitive functions” (Clare & Woods, 2004). The NIA (United States of America) identified cognitive training as an intervention aimed at preventing or delaying the onset of age-related cognitive decline, MCI, or clinical Alzheimer’s-type dementia (Kane et al., 2017). Additionally, the WHO ICOPE guidelines (http://www.who.int/ageing/publications/guidelines-icope/en/) recommend cognitive stimulation for older adults with cognitive impairment.
These interventions were assessed against outcomes that were judged as critical and important for this population.
Recommendations and Considerations
Recommendation
Cognitive training may be offered to older adults with normal cognition and with MCI to reduce the risk of cognitive decline and/or dementia.
Quality of evidence: very low to low
Strength of the recommendation: conditional
Supporting Evidence and Rationale
For cognitive stimulation versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Strout et al., 2016). No evidence for adults with MCI was available. The review reported that half of the interventions evaluated proved to be effective in improving cognitive outcomes in at least one cognitive domain – executive function, attention, memory, language and/or processing speed (Strout et al., 2016). The quality of the evidence was low. The results were reported in narrative form and no meta-analysis was conducted. No evidence for incident MCI or dementia was available.
For cognitive training versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Chiu et al., 2017). The review conducted a meta-analysis which showed that cognitive training in healthy older adults has a moderate positive effect on overall cognitive functioning. The quality of evidence was low. No evidence for incident MCI or dementia was available.
For cognitive training versus usual care or no intervention in adults with MCI, evidence was extracted from two systematic reviews (Chandler et al., 2016; Sherman et al., 2017). With regards to cognitive function outcome, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on cognition. With regards to incident dementia outcome, the quality of evidence is very low as the results were narratively reported. It was reported that one study found that half of the control group, but none of the intervention group, developed dementia at the 8-month follow-up, while another found that more of the intervention group reported incident dementia at the 2-year follow-up (Chandler et al., 2016). With regards to quality of life and functional level, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on ADL but not quality of life.
The evidence for cognitive interventions is mainly in studies with older adults. The GDG concluded that in this population the desirable effects of the intervention outweighed the undesirable effects and provided a conditional recommendation for cognitive training. The evidence for cognitive stimulation in reducing the risk of dementia was insufficient and no recommendation was made by the GDG.
3.6. Social Activity
For adults with normal cognition or MCI is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI
Intervention:
Comparison:
Care as usual or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
Social engagement is an important predictor of well-being throughout life (Cherry et al., 2011). Social disengagement conversely, has been shown to place older individuals at increased risk of cognitive impairment and dementia (Fratiglioni et al., 2004). A systematic review and meta-analysis of longitudinal cohort studies showed that lower social participation, less frequent social contact and loneliness were associated with higher rates of incident dementia (Kuiper et al., 2015).
The Lancet Commission on Dementia Prevention, Intervention, and Care identified social engagement as an intervention that could be used to prevent dementia (Livingston et al., 2017).
Recommendations and Considerations
Supporting Evidence and Rationale
For preservation and promotion of social activity including community and family engagement versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition (Kelly et al., 2017). No evidence for adults with MCI was available. For cognitive function outcomes, the quality of the evidence is very low. Three RCTs, which assessed the association between cognitive function and social activity, were deemed eligible. The review findings were reported narratively (Kelly et al., 2017). Overall cognition was measured by varied composite measures of global cognition, including the ADAS-cog, MMSE and MDRS. One of the three RCTs found social activity intervention to be significantly associated with improvements in cognitive function (Pitkala et al., 2011). No data were available for incident MCI or dementia, quality of life, functional level (ADL, IADL), adverse events or drop-outs.
The GDG concluded that the evidence is limited and inconclusive, so no recommendation was made for social activity and risk of cognitive decline/dementia. Furthermore, there is a risk of bias arising from reverse causality whereby low social engagement prior to diagnosis of cognitive decline or dementia may be at least in part due to the disease process. The GDG did not make a recommendation against social activity as they concluded that social activity has a wide range of other benefits to health and well-being.
3.7. Weight Management
For adults with normal cognition or MCI who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI who are overweight or obese
Intervention: Weight management
Non-pharmacological interventions, e.g. cognitive behavioural intervention strategies, lifestyle interventions
Pharmacological interventions, e.g. weight loss medication (e.g. orlistat)
Comparison:
Care as usual or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
Overweight and obesity are some of the best characterized and established risks for a variety of NCDs, responsible for at least 2.8 million deaths each year worldwide, and of an estimated 35.8 million (2.3%) of global disability-adjusted life years (DALYs) (WHO, 2019b). In 2008, 35% of adults aged 20+ were overweight (BMI ≥ 25 kg/m2) (34% men and 35% of women), with significantly variable prevalence among world areas, with the United States of America, Europe and the Eastern Mediterranean regions with the highest concentration of people with overweight/obesity (WHO, 2019b). Overweight and obesity, in particular, have been linked to a number of medical complications such as Type 2 diabetes (Chan et al., 1994), cancer (Renehan et al., 2015), premature mortality (Fontana & Hu, 2014), and CVD (Eckel, 1997), both as direct risk factors as well as risks for other cardiovascular risk factors, such as high cholesterol and hypertension.
Obesity has been steadily rising, particularly among older adults in the last few decades (Nguyen & El-Serag, 2010) and although an increasing body of evidence suggests that overweight (25 < BMI < 30) in older adults could be more protective than normal weight in terms of overall mortality (Flicker et al., 2010), a link has also been established between excess of fat body mass and cognitive impairment (Xu et al., 2011). A recent systematic review and meta-analysis of observational studies conducted on a total of about 600 000 individuals showed that obesity (but not overweight) at mid-life increases the risk of dementia (RR = 1.33; 95% CI: 1.08–1.63) (Albanese et al., 2017).
It has been suggested that weight loss could indirectly reduce the risk of dementia by improving a variety of metabolic factors linked with the pathogenesis of cognitive impairment and dementia (i.e. glucose tolerance, insulin sensitivity, blood pressure, oxidative stress, and inflammation) (Bennett et al., 2009). However, a direct beneficial effect of weight reduction intervention is also plausible. Although, so far, evidence of potential cognitive benefits of weight loss seem to be strongly associated with increased physical activity (Colcombe et al., 2006; Erickson et al., 2010), in 2011 a systematic review concluded that intentional weight loss can improve performance in some cognitive domains, at least in people with obesity (Siervo et al., 2011).
Recommendations and Considerations
Recommendation
Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia.
Quality of evidence: low to moderate
Strength of the recommendation: conditional
WHO guidance on overweight and obesity outlined in Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (2012) (http://www.who.int/nmh/publications/phc2012/en/)
WHO guidance on overweight and obesity should be followed.
Advise overweight patients to reduce weight by following a balanced diet.
Advise patients to give preference to low glycaemic-index foods (beans, lentils, oats and unsweetened fruit) as the source of carbohydrates in their diet.
Advise patients to reduce sedentary behaviour and practise regular daily physical activity appropriate for their physical capabilities (e.g. walking).
Additional considerations include:
Lifestyle interventions that included both diet and physical activity components seemed to show the best results.
In addition to interventions at individual level, lifestyle interventions at the population level, such as activity parks, green spaces and infrastructure to support active commuting, need to be considered.
Being underweight in both late-mid-life and old age might be associated with a higher risk of dementia. However, it is likely that this association is explained, at least in part, by reverse causality, whereby brain pathology may cause weight loss before the clinical onset of dementia.
Unintentional weight loss and malnutrition are associated with poor health outcomes and should be investigated and treated at all ages. However, it is unlikely that interventions that favour weight gain in people who are underweight in either mid- or late life can reduce the risk of dementia or cognitive impairment.
Supporting Evidence and Rationale
For weight reduction with behavioural and/or lifestyle interventions (or control of obesity) compared with usual care or no intervention, evidence was extracted from one systematic review examining adults with normal cognition who are overweight or obese (Veronese et al., 2017). No evidence for adults with MCI was available. There was low to moderate evidence that lifestyle interventions aimed at weight reduction could improve cognitive function in the attention, memory and language domains. Interventions were very short (ranging from 8 to 48 weeks). No data were found in relation to incident MCI and dementia outcomes. No evidence of adverse events was identified.
For pharmacological interventions for weight reduction (or control of obesity) compared with usual care or no intervention, no systematic reviews were found.
The GDG concluded that the benefits of the interventions outweighed the harms and provided a conditional recommendation. Since the observational evidence of a correlation between overweight/obesity and increased risk of dementia is stronger and more consistent in mid-life than in late life (Hersi et al., 2017; Lafortune et al., 2016; Pedditzi et al., 2016; Prickett et al., 2015; Xu et al., 2015), the GDG made a conditional recommendation for this population.
3.8. Management of Hypertension
For adults with normal cognition or MCI and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia?
Population:
Adults with normal cognition or MCI with hypertension
Intervention:
Antihypertensive medication, lifestyle interventions
Comparison:
Placebo/no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
Hypertension in mid-life has been associated with an increased risk of late life dementia (Kivipelto et al., 2001). In particular, a pattern of increased blood pressure during mid-life followed by a rapid decrease in blood pressure later in life has been found in individuals who go on to develop dementia (Kivipelto et al., 2001; Launer et al., 2000; Stewart et al., 2009).
There is mixed evidence relating to the reduction of blood pressure in late mid- or late life and subsequent cognitive decline or dementia, however, there is evidence to show that the reduction of hypertension can have substantial benefits in reducing cardiovascular morbidity and mortality and thus improving overall health of the ageing population (Musini et al., 2009).
Hypertension can be prevented through a range of lifestyle factors, including eating a healthy diet, maintaining a healthy weight and participating in an adequate amount of physical activity. It can also be controlled through antihypertensive medication. However, the evidence for the effectiveness of blood pressure lowering treatments in reducing the risk of cognitive decline and dementia risk is mixed.
Recommendations and Considerations
Recommendation 1
Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines.
Quality of evidence: low to high (for different interventions)
Strength of the recommendation: strong
Recommendation 2
Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia.
Quality of evidence: very low (in relation to dementia outcomes)
Strength of the recommendation: conditional
HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols
Medications used to treat hypertension
Notes on specific hypertension medications
Pregnant women and women of childbearing age not on effective contraception should not be given ACE inhibitors, ARBs or thiazide/thiazide-like diuretics; CCBs should be used. If not controlled with intensification dose of medication, refer to specialist.
Beta blockers are not recommended as first-line therapy. If a heart attack has been diagnosed within the previous three years, or there is atrial fibrillation or heart failure, then a beta blocker should be added to the starting dose of antihypertensive medication. Patients with angina may also benefit from treatment with a beta blocker.
Other treatment considerations
If there is a prior heart attack or stroke, or the person is otherwise at high risk of CVD, start a statin at the same time as starting antihypertensive medication. (Statins should not be used in women who are or who may become pregnant.)
If there is a prior heart attack or ischemic stroke, start low-dose aspirin.
The hypertension protocols included in this module serve well for initiation and maintenance of successful treatment. If there are serious adverse events, lack of control of blood pressure, or if a major medical event intervenes, then referral to a specialist will be needed.
If the patient is already on another medication regimen, blood pressure is controlled to the target level, and the medications the patient is taking are accessible and affordable, there is no reason to change the regimen.
If the patient feels faint on standing, check blood pressure while standing. If the systolic blood pressure is consistently less than 110 mm Hg in a patient on medical treatment, consider reducing the dosage or number of medications used.
Supporting Evidence and Rationale
For treatment of hypertension in the form of antihypertensive medication versus placebo or no intervention, evidence was extracted from two systematic reviews examining adults with normal cognition and hypertension (Parsons et al., 2016; Weiss et al., 2016). No evidence for adults with MCI was available. With regard to cognitive function and incident dementia outcomes, the quality of the evidence was low, which showed that antihypertensive therapy has no effect on cognitive decline or incidence of dementia. With regard to quality of life and functional level outcomes, the quality of evidence is very low, showing that antihypertensive therapy does not decrease quality of life or functional level. With regard to adverse events, the quality of evidence was very low, showing mixed findings with regard to antihypertensive use. There were no data on incident MCI and overall dropout rates. Initial results from the SPRINT-MIND trial, a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) that aims to evaluate the effect of intensive blood pressure control on risk of dementia, support the possibility of a dose-response relationship between blood pressure and risk of cognitive decline or dementia (SPRINT-MIND 2019). Observational evidence suggests a strong association between hypertension and incident cognitive decline/dementia.
For treatment of hypertension in the form of lifestyle interventions versus placebo or no intervention, no systematic reviews were found.
The GDG made a strong recommendation for management of hypertension for its established health benefits and a conditional recommendation for hypertension management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence that treatment of hypertension reduces the risk of cognitive decline or dementia, the benefits outweighed the harms since the evidence suggests that intervention does not lower quality of life or functional level and there are mixed results regarding adverse effects which may depend on the drug used. Additionally, robust evidence for a causal relationship is available.
3.9. Management of Diabetes
For adults with normal cognition or MCI and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI with diabetes mellitus
Intervention:
Comparison:
Placebo/no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
The presence of late life diabetes has been linked to an increased risk of dementia (Luchsinger, 2010; Prince et al., 2014; Profenno et al., 2010). However, the mechanism by which this occurs is unclear. Poor glucose control has been associated with lower cognitive functioning and greater cognitive decline (Yaffe et al., 2012). In addition, the complications associated with diabetes, such as nephropathy (kidney damage), retinopathy (eye damage), hearing impairment and CVD, have all been found to increase the risk of dementia (Bruce et al., 2014; Exalto et al., 2013).
The literature examining interventions that aim to improve glycaemic control shows mixed findings with regard to cognitive outcomes (Launer et al., 2011; Luchsinger et al., 2011). In addition, the evidence on the effectiveness of medication for diabetes in reducing dementia risk is inconsistent (Cheng et al., 2014; Moore et al., 2013; Parikh et al., 2011). There is some evidence to suggest that treating the cardiovascular comorbidities associated with diabetes, such as high cholesterol and hypertension, may mediate the risk for dementia (Johnson et al., 2012; Parikh et al., 2011).
Recommendations and Considerations
Recommendation 1
Management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines.
Quality of evidence: very low to moderate (for different interventions)
Strength of the recommendation: strong
Recommendation 2
Management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia.
Quality of evidence: very low
Strength of the recommendation: conditional
For individuals with diabetes, the WHO guidelines recommend the following treatments:
Type 2 diabetes
Oral hypoglycaemic agents for Type 2 diabetes, if glycaemic targets are not achieved with modification of diet, maintenance of a healthy body weight and regular physical activity (Level 1).
Metformin as initial drug in overweight patients (Level 1) and non-overweight (Level 4).
Other classes of antihyperglycaemic agents, added to metformin if glycaemic targets are not met (Level 3).
Reduction of cardiovascular risk for those with diabetes and 10-year cardiovascular risk > 20% with aspirin, angiotensin converting enzyme inhibitor and statins (Level 1).
Supporting Evidence and Rationale
For treatment of diabetes in the form of medications for glycaemic control versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Areosa Sastre et al., 2017). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and very low for incident dementia outcomes, which showed intensive as opposed to standard glycaemic control has an unclear effect on cognitive function and no effect on incident dementia. The evidence reviewed included data from a large study set across 215 collaborating centres in 20 countries in Asia, Australasia, Europe and North America. The quality of evidence for adverse events was very low, showing intensive glycaemic control increases the risk of hypoglycaemic events. No data on incident MCI, quality of life, functional outcomes or drop-out rates were available. Overall, in adults with normal cognition, the evidence may favour standard glycaemic control because intense glycaemic control has no effect on cognitive function but may result in increased episodes of hypoglycaemia.
For treatment of diabetes in the form of diet and life-style interventions versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Podolski et al., 2017). No evidence for adults with MCI was available. The quality of evidence was very low and the findings were mixed. No meta-analysis was conducted and there were no robust data on clinical significance.
The GDG made a strong recommendation for management of diabetes for its established health benefits and a conditional recommendation for diabetes management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence on the management of diabetes to reduce the risk of cognitive decline or dementia, the benefits outweighed the harms and there is robust observational evidence to suggest diabetes increases the risk of cognitive decline and dementia.
3.10. Management of Dyslipidaemia
For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI with dyslipidaemia
Intervention:
Comparison:
Placebo or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
Elevated serum cholesterol is one of the key modifiable cardiovascular risk factors. A third of ischaemic heart disease worldwide is attributable to dyslipidaemia and it is estimated to be the cause of 2.6 million deaths (4.5% of total) per year, as well as a considerable proportion of disability (WHO, 2019b). The prevalence of raised total cholesterol among countries seems to correlate with wealth: in high-income countries, more than 50% of adults have elevated total cholesterol level, more than double the rate in low-income countries (WHO, 2019c).
The idea that raised level of blood cholesterol could be related to an increased risk of dementia was already introduced in the mid-1970s (Richardson et al., 2000). Since then, a number of epidemiological studies have demonstrated a close relationship between high serum cholesterol levels and the onset of AD/dementia (Kivipelto et al., 2002; Solomon et al., 2007; Whitmer et al., 2005), but results have been inconsistent, with other studies showing no or negative correlation (Mainous et al., 2005; Mielke et al., 2005).
Based on the severity of the dyslipidaemia and CVD overall risk, lifestyle or pharmacological approaches can be undertaken to reduce blood cholesterol. Weight reduction and decreasing saturated fats in the diet (decreasing the consumption of food of animal origin) are the most common and effective lifestyle recommendations (Perk et al., 2012). However, dyslipidaemia is often controlled and managed pharmacologically, with statins being the drugs of first choice. Several observational studies have investigated the possible beneficial effect of statins therapy in preventing dementia, but bias and heterogeneity hampered the overall quality of the evidence (Song et al., 2013; Swiger et al., 2013; Wong et al., 2013). Recently, a re-analysis of statin use in AD patients from failed clinical trials suggested that the use of simvastatin may slow the progression of cognitive decline in some people (Geifman et al., 2017).
Recommendations and Considerations
Recommendation
Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia.
Quality of evidence: low
Strength of the recommendation: conditional
Additional considerations include:
Statin treatment in older adults should not be specifically initiated for preventing cognitive decline and/or dementia but may be used for other health benefits according to WHO’s
Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (
http://www.who.int/nmh/publications/phc2012/en/).
Supporting Evidence and Rationale
For control of dyslipidaemia through treatment with statins compared with placebo, evidence was extracted from one systematic review examining adults with normal cognition and dyslipidaemia (McGuinness et al., 2016). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and low for incident dementia outcomes, showing that treatment with statins has no effect on either incident dementia and/or cognitive decline. There is moderate quality evidence that the treatment with statins does not increase the incidence of serious adverse events.
A large body of observational evidence has linked dyslipidaemia to an increased risk of dementia and/or cognitive decline and found an association between control of dyslipidaemia and reduction of dementia and/or cognitive decline risk (Geifman et al., 2017; Hersi et al., 2017; Reitz, 2013; Song et al., 2013). Overall, indirect evidence suggests that managing dyslipidaemia in mid-life can help reduce the risk of cognitive decline and/or dementia.
No studies were identified that specifically aimed at controlling dyslipidaemia through lifestyle interventions and included outcomes related to dementia and/or cognitive impairment.
The GDG concluded that the desirable effects of dyslipidaemia treatment outweigh the undesirable effects and made a conditional recommendation.
The observational evidence reported a stronger correlation between high cholesterol and dementia in mid-life rather than late life (Hersi et al., 2017; Reitz, 2013). The systematic review evidence that focused on clinical trials in older adults (65+) showed that statin treatment has no effect on cognition or dementia outcomes (McGuinness et al., 2016). Therefore, the GDG concluded that there were no grounds to recommend the use of statin and the control of cholesterol in late life but only in mid-life.
3.11. Management of Depression
For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI with moderate to severe depressive disorder
Intervention:
Pharmacological interventions to treat depression (antidepressant medication)
Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation)
Comparison:
Care as usual or placebo or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
There is a substantial body of evidence linking depression to cognitive decline and dementia. A review carried out as part of the World Alzheimer Report in 2014 combined 32 studies into a meta-analysis which looked at the effect of depression on the risk of incident dementia. This involved 62,568 participants with a median follow-up of 5 years (range 2 to 17). The review reported that the presence of depression nearly doubled the risk of dementia (pooled effect size = 1.97, 95% CI: 1.67–2.32) (Prince et al., 2014).
The authors also carried out a meta-regression looking at follow-up time. They reported a trend toward smaller effect sizes in studies with longer follow-up suggesting that depression may have a prodromal role in dementia. It is noteworthy to mention that cognitive impairment may be the main symptom of depression in the elderly; a phenomenon that used to be called pseudodementia.
There are several potential explanations for the link between depression and cognitive impairment or dementia. Some of these include associations between depression, noradrenergic changes and white matter lesions, depression which stems from insight into impairment at early stages of decline, depression highlighting underlying deficits, i.e. by reducing motivation and bringing its own cognitive deficits (Camus et al., 2004; Jorm, 2001; Kales et al., 2005; Schweitzer et al., 2002).
Recommendations and Considerations
There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia.
The management of depression, in the form of antidepressants and/or psychological interventions, should be provided to adults with depression according to existing WHO mhGAP guidelines.
WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings
For adults with moderate to severe depressive disorder, the WHO guidelines recommend the following treatments:
Psychosocial/non-pharmacological treatment and advice
Psychoeducation (for the person and his or her family, as appropriate).
Addressing current psychosocial stressors.
Reactivate social networks.
Brief psychological treatments, if available.
Offer regular follow-up.
Antidepressant medication
Select an antidepressant from the National or WHO Formulary. Selective serotonin reuptake inhibitors (fluoxetine) and tricyclic antidepressants (amitriptyline) are antidepressants mentioned in the WHO Formulary and are on the WHO model list of essential medicines.
In selecting an antidepressant, consider the symptom pattern of the person, the side-effect profile of the medication, and the efficacy of previous antidepressant treatments, if any.
For co-morbid medical conditions, before prescribing antidepressants, consider potential for drug-disease or drug-drug interaction. Consult the National or the WHO Formulary.
Combining antidepressants with other psychotropic medication requires supervision by, or consultation with a specialist.
Supporting Evidence and Rationale
For pharmacological interventions to treat depression (antidepressant medication) compared with usual care or placebo, evidence was extracted from one systematic review examining adults with normal cognition and major depressive disorder (Baune et al., 2018). No evidence for adults with MCI was available. The review conducted a network meta-analysis and reported standardized mean differences in the Digit Symbol Substitution Test as a measure of cognition function. The review reported that vortioxetine (versus placebo) improved cognitive functioning while duloxetine, sertraline, citalopram, escitalopram, phenelzine and nortriptyline showed no effect (Baune et al., 2018). The quality of the evidence was very low and no data were reported for incident MCI or dementia outcomes, quality of life, adverse events, functional level or drop-out rates. Overall, the true balance of effects is difficult to ascertain. The evidence favours the use of vortioxetine (but not other pharmacological interventions) to treat depression for reducing the risk of cognitive decline or dementia. However, no data on adverse effects were available, e.g. drug-related side-effects or interactions.
For psychological interventions to treat depression compared with placebo or no intervention, no relevant systematic reviews were found.
The GDG therefore concluded that there was insufficient evidence currently for depression management and reduction of risk of cognitive decline/dementia. They also concluded that the management of depression is important for its other benefits and did not make a negative recommendation against this intervention.
3.12. Management of Hearing Loss
For adults with normal cognition or MCI and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia?
Population:
Adults with normal cognition or MCI with hearing loss
Intervention:
Interventions to treat hearing loss (e.g. hearing aids)
Comparison:
Care as usual or no intervention
Outcomes:
Critical
- –
Cognitive function
- –
Incident MCI
- –
Dementia
Important
- –
Quality of life
- –
Functional level (ADL, IADL)
- –
Adverse events
- –
Drop-out rates
Background
Hearing loss is a prevalent age-related disorder. As the fourth leading cause of years lived with disability in the global population (WHO, 2012), it is estimated to affect one in three adults aged 65 and older, with this statistic growing annually (Wilson et al., 2017). The implications of hearing loss, however, are often underestimated both at the individual and population level (Blustein et al., 2018).
Hearing impairment has debilitating consequences on functional ability and social and emotional well-being. Deteriorations in hearing impact on individuals’ ability to communicate with others, which in turn can result in feelings of frustration, isolation, loneliness (Ciorba et al., 2012). Older adult populations who already experience the isolating effects of age-related factors, such as diminished mobility, driving cessation, death of partners or living alone, are particularly vulnerable to these psychosocial impacts.
Hearing loss is also associated with increased risk of cognitive decline or dementia (Lin et al., 2013). A recent meta-analysis of prospective cohort studies showed that the relative risk of hearing impairment on incident Alzheimer’s and MCI was 2.82 (95% CI: 1.47–5.42). (Zheng et al., 2017). Additionally, a meta-analysis published by the Lancet Commission showed that hearing loss can almost double the risk of incident dementia (RR = 1.94, 95% CI: 1.38–2.73) (Livingston et al., 2017). Hearing loss and cognitive impairment or dementia, individually, and in combination, predict functional ability and burden of care. Hearing loss interventions, therefore, have the potential to substantially improve outcomes for older people on multiple domains.
Recommendations and Considerations
There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia.
Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines.
WHO Guidelines on integrated care for older people (ICOPE)
For older adults, WHO recommends the following:
Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss.
Considerations for recommendation
Community awareness about hearing loss and the positive benefits of audiological rehabilitation in older people, through community case finding and outreach activities, should be promoted.
Health care professionals should be encouraged to screen older adults for hearing loss by periodically questioning them about their hearing. Audiological examination, otoscopic examination and the whispered voice test are also recommended.
Hearing aids are the treatment of choice for older people with hearing loss, because they minimize reduction in hearing and improve daily functioning.
Medications should be reviewed for potential ototoxicity.
People with chronic otitis media or sudden hearing loss, or who fail any screening tests, should be referred to an otolaryngologist.
Supporting Evidence and Rationale
For interventions to treat hearing loss (e.g. hearing aids) versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and hearing loss (Cherko et al., 2016). No evidence for adults with MCI was available. For cognitive function and quality of life, the quality of evidence is very low. No meta-analyses were performed and results were reported narratively with no numerical data to support conclusions (Cherko et al., 2016). Based on two studies including measures of cognitive function, the review concluded that while hearing aids use was found to be associated with improvements in cognitive function, these benefits may be limited in that cognitive improvements have been shown to revert to baseline at 1 year follow-up. They also concluded that use of hearing aids in older people was associated with improvements in quality of life outcomes based on two studies. Overall, the evidence does not favour either the intervention or the comparison. Hearing aids may improve quality of life but the amount of evidence available is limited. No data are available for incident MCI or dementia, functional level (ADL, IADL), adverse events or drop-outs.
The GDG concluded that there is currently insufficient evidence to recommend the use of hearing aids to reduce the risk of cognitive decline/dementia. The GDG also concluded that the use of hearing aids is important to correct hearing loss in older adults for their other benefits and recommend following the ICOPE guidelines in this regard.
