ISSUES IN STUDYING RISK AND PROTECTIVE FACTORS AND INTERVENTIONS

This report uses a health promotion approach because such an approach is applicable to broad community-based populations and also applicable across the life span. Efforts to promote cognitive health should begin early to have maximal benefit. Discussions about prevention become complex because cognitive aging is not a disease but rather is a highly variable process of cognitive change as individuals get older.

Further complicating discussions of risk and protective factors for cognitive aging is the intertwined and not fully understood nature of the relationship between medical conditions that may result in short-term cognitive decline (e.g., stroke, delirium, and medications that compromise cognition) and cognitive aging over time. Although some individuals with acute decline may return to their baseline level of cognitive functioning, others may make only a limited recovery, and still others may find that their cognitive function does not improve at all; the long-term impacts of acute cognitive decline on cognitive aging are not fully understood. Furthermore, much of the literature on medical-related risk factors has focused on neurodegenerative diseases and less research on these factors has been devoted to cognitive aging per se.

One of the overriding issues in assessing the role of risk factors as correlates or determinants of cognitive aging is the socioeconomic status (SES) of the individual or the group of interest (Deary, 2012). SES is often measured by an individual's social status, educational attainment, occupational level, and income. Importantly, it is one of the strongest correlates of cognitive status, performance, and outcomes, and these associations persist across the life span (Kuh et al., 2014). SES is also correlated with many other health states and outcomes, including those related to infant and childhood developmental outcomes, and thus it is an important consideration—both as a determinant and a confounder of associations—in any analysis and interpretation of cognitive aging studies of risk and intervention programs (Wong and Edwards, 2013). In many instances, SES is likely to be a surrogate for various environmental and genetic exposures, which, if possible, should be identified.

Because of the limited number of available studies of any type on cognitive aging, the committee decided to include the wide range of available studies but also to note the challenges and limitations of the studies where relevant. Although often the available studies evaluate cognitive outcomes with only short-term follow-up and do not examine long-term cognitive aging trajectories, the committee determined that since the short-term cognitive effects are potentially preventable, they should be noted in this report.

In compiling the evidence for each of the relevant factors and interventions, the committee did not conduct new systematic reviews of primary evidence. It based its assessments on existing systematic reviews, updated literature reviews, original articles, clinical guidelines, and input from experts. The goal was to create a synthesis of the evidence that would be sufficient to guide recommendations on important risk factors and on the interventions to address them. While this report's focus is on cognitive aging, some of the included studies addressed the outcomes of cognitive impairment, dementia, and Alzheimer's disease.

One major effort to evaluate recent studies that have examined modifiable risk factors for cognition and dementia reviewed 247 studies published between January 1990 and October 2012, each of which included at least 300 generally healthy people and used either a cross-sectional or a prospective (longitudinal) study design (Beydoun et al., 2014a). The authors considered all cognitive outcomes, including global and domain-specific cognitive outcomes, cognitive decline, prevalent and incident mild cognitive impairment (MCI), dementia, and Alzheimer's disease. A variety of modifiable risk factors was considered, including education, physical activity, and nutrition. The committee drew on this comprehensive review when summarizing the available evidence on modifiable risk factors, but also examined other reviews pertinent to individual risk factors as well as primary studies. The committee recognized a number of methodological challenges, which are described in subsequent sections.

PHYSICAL ACTIVITY AND EXERCISE

Physical activity is strongly linked to healthy aging and remaining independent, and it has been associated with helping individuals maintain their physical and cognitive function throughout life and also with older adults developing fewer chronic conditions (Lee at el., 2012; NIH, 2014b). Conversely, ample evidence suggests that low levels of physical activity are associated with an increased risk of developing a number of diseases including stroke, hypertension, type 2 diabetes, osteoporosis, and a variety of cancers including colon and breast cancer (Lee et al., 2012).

Evidence from Observational Studies

The relationship between physical activity and cognitive heath has been studied over decades. In the 1970s Spirduso and colleagues compared the performance of younger and older individuals, both athletes and non-athletes, on a series of reaction time and movement tasks (Spirduso, 1975; Spirduso and Clifford, 1978) and observed that older athletes outperformed older non-athletes on many of these tasks. These results, and others, led to a multitude of cross-sectional studies that generally found older high-fit individuals to perform better than low-fit adults on a number of perceptual, cognitive, and motor tasks (Abourezk and Toole, 1995; Clarkson-Smith and Hartley, 1990). Longitudinal observational studies have also generally found a relationship between physical activity and cognitive health outcomes. For example, Zhu and colleagues (2014) found that a graded exercise measure of cardiorespiratory fitness predicted performance on a variety of cognitive tasks 25 years after the original measurement, even after accounting for differences in participants' race, sex, age, and education.

Several recently published systematic reviews (Anderson et al., 2014; Beydoun et al., 2014b; Blondell et al., 2014), as well as many qualitative reviews (Ahlskog et al., 2011; Bherer et al., 2013; Bielak, 2010; Lautenschlager et al., 2012), have reiterated these findings. A 2014 review included 21 prospective studies on physical activity and cognitive decline and 26 prospective studies on physical activity and dementia (Blondell et al., 2014). A meta-analysis was conducted on these studies, and as shown in Figure 4A-1, the majority showed benefit, with the overall finding that physically active adults had a 35 percent lower risk of cognitive decline (relative risk [RR] = 0.65; 95% confidence interval [CI] 0.55–0.76) than those who were inactive.

FIGURE 4A-1

Studies on physical activity and cognitive decline. SOURCE: Blondell et al., 2014.

Studies with the highest-quality, longest follow-ups, and with a greater number of adjustments for differences between study designs, have yielded findings about the value of exercise that are more conservative but still in the protective direction (Blondell et al., 2014). In the Study of Osteoporotic Fracture, women who reported more physical activity at any time in their life course (adolescence and at age 30 years, 50 years, or in later life) had lower risk of cognitive impairment than inactive women; the association was especially strong for women who had been active teenagers (Middleton et al., 2010). In a recent systematic review, 21 of 24 prospective studies found an association between physical activity and cognitive outcomes, and all four of the cross-sectional reports included did so as well (Beydoun et al., 2014b).

EDUCATION AND INTELLECTUAL ENGAGEMENT

Educational attainment is a well-known demographic characteristic that is correlated with peak cognitive ability, and inversely correlated with cognitive decline and dementias, including Alzheimer's disease. Low literacy and low educational attainment often reflect, in part, adverse early life conditions that may have deleterious effects on cognitive abilities throughout life. Educational attainment is one of the easiest and most consistently evaluated measures of SES. However, the challenge with studies on education and cognitive aging is clarifying the cause and effect (EClipSE Collaborative Members et al., 2010). Many midlife and older adults are involved in a wide variety of intellectual activities that extend beyond traditional education, including taking college or enrichment courses, reading, learning new languages or musical instruments, and doing crossword puzzles or other types of efforts to learn more or challenge themselves. The extent and impact of these efforts on cognitive aging is not fully known (ACE and MetLife, 2007).

Higher levels of education may allow older people to perform better on cognitive tests (Meng and D'Arcy, 2012) and may provide a buffer against cognitive decline. This finding is consistent with the concept of “cognitive reserve.” As noted in Chapter 2, cognitive reserve is a theoretical concept proposing that certain lifetime experiences, including education, degree of literacy, and occupational attainment, increase the flexibility, efficiency, and capacity of brain networks, thereby allowing individuals with higher cognitive reserve to sustain greater levels of brain pathology before showing clinical impairment (for a review of cognitive reserve, see Stern, 2009). Supporting the concept of cognitive reserve, cross-sectional studies of nondemented and demented individuals have reported greater levels of brain atrophy among individuals with higher cognitive reserve than among those with lower cognitive reserve and similar levels of cognitive functioning, suggesting that the effects of atrophy on cognition are reduced in individuals with higher reserve (Arenaza-Urquijo et al., 2013; Liu et al., 2012; Querbes et al., 2009; Reed et al., 2010; Sole-Padulles et al., 2009). In older adults without dementia, studies suggest that education is strongly associated with cognitive performance globally, as well as in many specific domains, but that it is not associated with the rate of cognitive decline (Singh-Manoux et al., 2011; Zahodne et al., 2011). Thus, cognitive reserve appears to delay the onset of the clinical signs of dementia, including Alzheimer's disease, while in cognitively healthy people, it is associated with higher cognitive performance throughout life but no difference in the rate of cognitive decline with aging.

Cross-sectional studies of older adults have also shown positive relationships between literacy and cognitive performance even after adjusting for level of education (Albert and Teresi, 1999; Federman et al., 2009; Jefferson et al., 2011). Two longitudinal studies evaluated the association between literacy and cognitive decline in aging and found that, even after controlling for education, individuals with lower literacy showed greater declines in memory, language, and executive functioning (Manly et al., 2003, 2005). Furthermore, literacy has been shown to help explain difference between black and white older adults in both cognitive performance and rates of cognitive decline, again after controlling for education (Mehta et al., 2004; Sachs-Ericsson and Blazer, 2005).

More highly educated people also typically have lower risk of cardiovascular disease and engage in healthier behaviors; these differences can translate into more favorable cognitive trajectories during adulthood (Hendrie et al., 2006). However, race/ethnicity, country of origin, cultural diversity, and language fluency also relate to educational attainment and the ability to score well on cognitive tests, making it extremely difficult to disentangle the influence of these various factors. In a systematic review, 18 of 27 prospective studies and 21 out of 25 cross-sectional studies found that lower educational attainment was associated with worse cognitive outcomes (Beydoun et al., 2014a).

Some studies have addressed the impact of intellectual engagement and lifelong learning on cognitive outcomes. Such studies often record individuals' self-report of intellectually challenging activities at one point in time and compare the number and frequency of these activities with measures of cognition or the diagnosis of neurodegenerative disorders years later. In a study of 294 older adults, Wilson and colleagues (2013) found that greater cognitive activity in early life (e.g., reading books, visiting a library, writing letters, etc.) was associated with a lower rate of cognitive decline later in life. This relationship (increased activity early in life associated with decreased rate of cognitive decline at a later time) remained when cognitive declines associated with neuropathology were removed from the equation. These results might be viewed as an example of cognitive reserve—that is, an enhancement of cognition either earlier in life or in late life that serves as a protective factor with aging (Stern, 2012; see Chapter 2). In examining data on intellectual engagement and lifelong learning efforts (midlife and later life) in participants of the Mayo Clinic Study of Aging (a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota), researchers found that intellectually related efforts may have protective effects on cognitive aging (Geda et al., 2011; Vemuri et al., 2014). There are also ongoing studies comparing cognitive training and cognitive engagement activities (Stine-Morrow et al., 2014). The challenges of studies in this area include the many different types of activities that individuals engage in, the varying extent to which these activities are engaged in by individuals, and the long-term nature of follow-up. Many of these studies are observational, and while they are important in establishing the relationship between cognitively stimulating activities and cognitive decline or age-related neurodegenerative diseases, they do not establish causality.

SOCIAL ISOLATION, LONELINESS, AND SOCIAL ENGAGEMENT

DIET

Various dietary patterns have been studied in the hope of identifying nutritional approaches to preserving brain function and preventing cognitive decline. Among these are diets characterized by a higher intake of fruits and vegetables and a lower intake of meat, including the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet.

Mediterranean diets, based on the dietary patterns prominent in countries bordering the Mediterranean Sea, emphasize:

• a high consumption of fruits, vegetables, cereals, and legumes;
• a moderate consumption of fish and alcohol, especially red wine; and
• a low consumption of saturated fats (with olive oil as the main source) and dairy products (with yogurt and cheese as the main sources).

The DASH diet emphasizes vegetables, fruits, and fat-free or low-fat dairy products. It includes whole grains, fish, poultry, beans, seeds, nuts, and vegetable oil, and it limits sodium, sweets, sugary beverages, and red meats. In terms of nutrition content, DASH is low in saturated and trans-fats and rich in potassium, calcium, magnesium, fiber, and protein (NIH, 2014a).

VITAMINS

Despite widespread publicity about the benefits of vitamins and supplements for brain health and the large expenditures made on these products for a wide variety of reasons (in 2012, $32.5 billion was spent on dietary supplements, including $13.1 billion for vitamin- and mineral-containing supplements [NIH, 2013]), the evidence for supplements enhancing cognition or preventing decline is limited. Much of the published literature is based on cross-sectional or longitudinal observational studies and few RCTs. In addition, methodological differences among the published studies hinder conclusions. These differences include variable doses of the nutrient, different timings of the intervention (e.g., midlife versus late life), different lengths of follow-up, variable adherence (for prospective studies), and variations in recall (for retrospective studies). The evidence base is further complicated by the fact that the same nutrient may have different effects when it is delivered as a supplement from when it is obtained through increased dietary intake. Similarly, foods and beverages may have other components (e.g., polyphenols in coffee) that may be at least partly responsible for an effect attributed to a particular item (e.g., caffeine). Moreover, supplements are not regulated by the Food and Drug Administration and may not be pure and may not contain consistent doses of the active ingredients.

ALCOHOL

Excessive alcohol consumption has detrimental effects on judgment and reaction times and can cause long-term cognitive damage (Bartley and Rezvani, 2012). The reasons for this include altered nutrition; the consequences of excessive alcohol consumption, such as cirrhosis; interactions with medications and other substances; and alcohol-associated injuries, such as those sustained in vehicular crashes. Furthermore, high levels of alcohol intake may be associated with psychiatric comorbidity, which also may have adverse cognitive consequences. Compared to either abstinence or excessive alcohol consumption, moderate drinking in adulthood—generally less than two drinks per day and in most populations much less than this—is associated with various health benefits such as the avoidance of heart disease and a lower mortality risk (Jayasekara et al., 2014; Roerecke and Rehm, 2012), although consideration needs to be given to baseline cognitive function (Krahn et al., 2003). This J- or U-shaped relationship between alcohol consumption and some health outcomes has been postulated to extend to cognitive aging and dementia. Possible mechanisms for the lower rates of cognitive and other impairments associated with moderate alcohol intake include decreased cardiovascular risk, improved lipid levels, the antioxidant properties of flavonoids found in red wine, lower platelet aggregation, improved insulin sensitivity, reduced inflammation, and possibly a direct effect of alcohol on cognitive function through acetylcholine release in the hippocampus that may improve learning and memory (Beydoun et al., 2014a; Peters et al., 2008a). Moderate, controlled intake may also be a behavioral indicator of personal control regarding risky behaviors. A 2008 systematic review examined 23 studies involving adults age 65 years and older (20 prospective and 3 case-control studies nested in a cohort) and found a nonsignificant pooled relative risk for cognitive decline (RR = 0.89; 0.67–1.17) (Peters et al., 2008a). In the NIA systematic review, 8 of 18 prospective studies found the J- or U-shaped association between moderate alcohol consumption and cognitive outcomes, as did 9 of 12 cross-sectional studies (Beydoun et al., 2014a).

Observational evidence suggests that light to moderate alcohol consumption is not a risk factor for the loss of cognitive function and may even be a protective factor throughout adulthood. However, the evidence base is insufficient to recommend an amount of alcohol intake, if any, that would be beneficial for cognition, particularly across the life span. Excessive alcohol consumption has well-established cognitive harms (Peters et al., 2008a).

SMOKING

Smoking is a strong risk factor for heart disease, stroke, cancer, lung disease, and many other chronic conditions (CDC, 2008). Its relationship to cognitive outcomes is complex. Given that smoking increases the risk of stroke, it would be expected also to increase the risk of vascular dementia and cognitive decline. However, the nicotine in cigarettes increases the release of acetylcholine, which improves attention and information processing (Beydoun et al., 2014a). Moreover, deficits in the cholinergic system are involved in Alzheimer's disease, and thus it has been suggested that smoking can delay Alzheimer's disease (Beydoun et al., 2014a). The death rate of smokers is three times that of non-smokers, and their life expectancy is shortened by approximately 10 years (Jha et al., 2013). Thus, it may be that the lower incidence of Alzheimer's disease among smokers is an artifact of their earlier deaths from other causes. Furthermore, systematic reviews have found that current smokers have an increased age-specific risk of Alzheimer's disease, vascular dementia, and other dementias (Peters et al., 2008b), while these risks were not significantly increased among former smokers.

In the NIA systematic review, 16 of 29 prospective studies observed associations between smoking and poorer cognitive outcomes, while four studies found associations with some outcomes or in some subgroups, and nine studies found no associations or associations in which smokers had better cognitive outcomes than non-smokers (Beydoun et al., 2014a). Only two of seven cross-sectional studies found associations of smoking with poorer cognitive outcomes. Several large studies have found associations with cognitive decline, dementia, and Alzheimer's disease in heavy smokers, but not in lighter smokers (Beydoun et al., 2014a).

To the committee's knowledge, no intervention trials have been conducted that manipulate smoking initiation or smoking cessation and then examine the effects on cognitive outcomes.

The evidence linking smoking to cognitive outcomes is mixed and inconclusive. Given the many health problems of aging smokers and the relationship of smoking to coronary disease, stroke, and dementias, there are ample reasons for current smokers to quit, despite the uncertainty about the cognitive benefits.

SUBSTANCE ABUSE

PHYSICAL ENVIRONMENT

Older people experience a number of general as well as occupational exposures that may adversely affect cognitive performance. The role of potentially adverse exposures that occur early in life on cognitive trajectories is often uncertain, in part because of the challenges of performing the critical research needed, but also because of the multiple confounding exposures and experiences that occur across a lifetime. However, middle-aged and older individuals may also have continuing environmental exposures that may alter their cognitive performance. Some of the more common and potentially important exposures are described here.

STRESS

With the publication of Hans Selye's letter to the journal Nature in 1936, the concept of “stress” became a subject of interest to researchers (Szabo et al., 2012). Early on, stress was defined non-specifically as the response of the body to a noxious stimulus, which later became known as “general adaptation syndrome” (Szabo et al., 2012). As the American Institute of Stress notes, “Stress is not a useful term for scientists because it is such a highly subjective phenomenon that it defies definition. And if you can't define stress, how can you possibly measure it?” (AIS, 2014). Thus, it is not surprising that the evidence relating stress to cognitive outcomes has been compiled in diverse ways and has produced results that are inconsistent and difficult to interpret. The “distress” encountered daily comes in many forms—from traffic congestion to the experience of having a bad boss to the death of a loved one—and it raises the question, “Does stress cause cognitive decline?” For this reason, the committee briefly addresses stress here, even though the current evidence base raises more questions than it answers.

Selye's original experiments were done with mice, and indeed a number of studies have assessed the effects of experimental stressors on cognition in laboratory settings. For example, it is known that in both monkeys and rodents, stress affects the pyramidal neurons in the prefrontal cortex, the same neurons that are affected by aging. The interactive effects of stress and aging in the rodent model were recently reviewed in detail (McEwen and Morrison, 2013).

In epidemiological studies, stress is frequently defined in terms of stressful life events (poor parenting in early life, divorce, loss of a job, or death of a loved one), and perceived stress is measured by various validated scales, or personality traits that make some people more vulnerable to stress than others. Finnish boys separated from their parents during World War II were found to have lower cognitive scores in several domains at age 60, with longer separations linked to greater deficits (Pesonen et al., 2007). The death of a child is a major life stressor associated with a faster rate of cognitive decline in later life (Comijs et al., 2011; Greene et al., 2014), especially when the loss occurred among parents who were young adults or had no subsequent children (Greene et al., 2014). However, the number and subjective ratings of stressful life events in the Cache County Study were associated only inconsistently with cognitive decline; stronger associations between stressful life events and cognitive decline were found in younger participants and those with less education (Tschanz et al., 2013). In the Longitudinal Aging Study Amsterdam, the death of a child or grandchild was associated with faster cognitive decline, and having experienced fewer major life events was associated with better cognitive function (Comijs et al., 2011).

Similarly, perceived daily stress has also been associated with greater memory problems among adults with cognitive decline (Rickenbach et al., 2014). Greater levels of perceived stress were also associated with lower initial cognitive performance and faster rates of decline among 6,207 older adults followed for almost 7 years in the Chicago Health and Aging Project (Aggarwal et al., 2014). Perceived social strain has been shown to elevate levels of cortisol (Friedman et al., 2012), a stress hormone and a marker of activation of the hypothalamic–pituitary–adrenal axis. Chronic activation of this axis has been associated with poor health outcomes, including cardiovascular disease, which could also further contribute to cognitive decline and dementia (Kremen et al., 2012).

Few intervention trials have been carried out with the goal of preserving cognition by modifying perceived stress or attempting to reduce stress responses during or after major life events. In a recent review of 12 studies of meditation and mindfulness and cognition in older people, 6 of which were randomized trials, meditation and mindfulness seemed to have benefits for a number of cognitive domains, but the trials were small and susceptible to bias (Gard et al., 2014). Major life events, as well as perceived stress and mild worry, have been associated with decreased cognitive performance and faster cognitive decline in several recent studies. Interventions that reduce the perceptions of stress or responses to it, such as meditation and mindfulness, may be helpful but require further study.

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Footnotes

1

These tasks included the critical flicker fusion test (the point at which the viewer perceives a flickering light source is a steady, continuous one, used as a measure of the brain's processing capacity), the digit symbol substitution test (which measures memory and processing speed), and the Stroop test (which also tests memory, processing, and executive brain functions) (Cohn et al., 1984; Rikli and Edwards, 1991).

2

The Experience Corps trains and places volunteers in elementary schools for an academic year and covers three areas: general literacy support, library support, and conflict resolution. It is designed to bolster memory and executive functions of the volunteers by reading with children, problem solving, and working with team members and through various program activities (Rebok et al., 2004).