Risk and Protective Factors and Interventions: Health and Medical Factors

Dan G. Blazer; Kristine Yaffe; Catharyn T. Liverman; Committee on the Public Health Dimensions of Cognitive Aging; Board on Health Sciences Policy; Institute of Medicine

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Committee on the Public Health Dimensions of Cognitive Aging; Board on Health Sciences Policy; Institute of Medicine; Blazer DG, Yaffe K, Liverman CT, editors. Cognitive Aging: Progress in Understanding and Opportunities for Action. Washington (DC): National Academies Press (US); 2015 Jul 21.

4BRisk and Protective Factors and Interventions: Health and Medical Factors

This is the second of three chapters exploring risk and protective factors and interventions relevant to cognitive aging. Chapter 4A discusses lifestyle factors and the physical environment, and Chapter 4C discusses general approaches to remediation and provides concluding remarks and recommendations on opportunities for next steps in promoting healthy cognitive aging.

This chapter addresses many of the external factors and comorbidities that may affect cognition. The basic overall challenge is that much more needs to be learned about how these factors affect cognitive aging—in particular, whether they have long-term effects on cognitive function. Some of these factors (e.g., certain medications, delirium) may result in easily identifiable short-term risks of cognitive declines, which in some cases it may be possible to completely reverse; in addition, these factors may mediate more long-term changes in cognitive trajectory. For other factors, such as comorbidities and exposures that occur over a period of years, research questions generally focus on the extent to which treating or reducing a comorbidity (e.g., diabetes or uncontrolled hypertension) or reducing or eliminating an exposure will affect long-term cognitive function. Further research is also needed on the biological mechanisms underlying the impact of these factors on cognitive change and the extent to which each is a cause or a mediator of change. As with all aspects of cognitive aging, cognitive function may vary widely both within an individual over time and among individuals.

Each section of this chapter focuses on a specific risk or protective factor and summarizes evidence from available observational studies and intervention studies, then concludes with a summary comment on the strength of the evidence.

MEDICATIONS

Increasingly, certain classes of medicines have been recognized as causing cognitive decline and impairment; these potentially preventable adverse events have risks that are a function of dose, duration, and individual susceptibility (such as preexisting cognitive impairment or dementia or genetic makeup). The impact of these medications on long-term cognitive function is an area of ongoing research.

The role of health care professionals who are interested in preventing adverse effects from medication is made more difficult by a steady influx of new knowledge about the effects and interactions of these medications, by the complex medication regimens that are required to treat many diseases, and by the multiple health care providers that are involved in the care of many older people. Not only is it challenging for health care professionals to stay up to date on the medications they prescribe and to manage medications for individual patients; it is also difficult for them to determine whether the medications they prescribed may have negative or positive cognitive effects when administered in conjunction with other medications. In the United States, older adults represent about 13 percent of the population but are prescribed more than 40 percent of drugs that are prescribed. On average, individuals from ages 65 to 69 years old are prescribed 14 different drugs per year (ASCP, 2015). The high rate of prescription drug use is associated with substantial rates of serious adverse drug events, which are considered preventable in 27 percent of ambulatory, 28 percent of hospitalized, and 42 percent of long-term care patients (Bates et al., 1995; Fick and Semla, 2012). Additionally, some medications with the potential for negative effects on cognition are available over the counter.

Evidence from Observational Studies

Although a number of studies have indicated that there may be an association between these drug classes and dementia, the potential for unrecognized dementia or other confounding conditions in many of these studies prevents the establishment of any causal relationship.

Beers Criteria Medications

Based on a comprehensive and systematic review and a guideline panel process which included the grading of evidence and a public comment period, the 2012 American Geriatrics Society's (AGS's) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommended that a number of drugs and classes of drugs be avoided in older adults because of their potential for causing cognitive decline or delirium (AGS, 2012; see Table 4B-1). While a detailed review of all of these drugs is beyond the scope of this report, the usage of anticholinergic and benzodiazepine drugs will be specifically addressed because they remain in common use and are especially at risk for inappropriate use by older individuals.

Anticholinergic Drugs (Including Antihistamines)

Depending on the population studied, about 20 to 50 percent of older persons in the United States are prescribed at least one anticholinergic drug at any given time (Campbell et al., 2009). While definite indications exist for these classes of drugs, such as for the treatment of allergies, nausea, depression, muscle spasm, and many other medical conditions, some of the usage may be inappropriate. Instead, effective less-toxic alternatives should be considered.

Several systematic reviews have documented the association of anticholinergic drugs with both short-term and long-term adverse cognitive effects in older adults (Campbell et al., 2009; Kalisch Ellett et al., 2014; Tannenbaum et al., 2012). Kalisch Ellet and colleagues (2014) analyzed Australian veterans' administrative claims data from 2010 to 2012 and found that using two or more anticholinergic medications increased the risk of hospitalization for confusion or dementia. A listing of drugs with strong anticholinergic properties is provided in Table 4B-2.

A clinical review of 27 studies that included anticholinergic assays and measurement of cognitive performance found that 25 showed associations between the anticholinergic activity of medications and delirium, cognitive impairment, or dementia (Campbell et al., 2009). In a large three-city population study of more than 6,900 older persons (Carriere et al., 2009), continuous anticholinergic drug use was found to be associated with a 1.4-to 2.0-fold higher risk of cognitive decline. In addition, the risk of incident dementia was also increased in continuous users over the 4-year follow-up period (hazard ratio 1.65, 95% confidence interval [CI] 1.0–2.7). The risk increased with the duration of continuous use and was also higher among those with baseline cognitive impairment and dementia (Tannenbaum et al., 2012).

Many antihistamines are available in over-the-counter preparations, including those used for cold, influenza, allergy relief, and sleep (“PM” formulations). Because these antihistamines, such as diphenhydramine, are potent anticholinergic agents, it is important to educate the general public about the potential risks, including the risk of cognitive decline.

Benzodiazepines

Commonly used to treat anxiety, sleeplessness, and agitation in older persons, benzodiazepines (e.g., alprazolam, lorazepam, chlorazepate, and clonazepam) are associated with a markedly increased risk for delirium, cognitive impairment, falls, fractures, and motor vehicle accidents (Billioti de Gage et al., 2012; de Vries et al., 2013). In a recent systematic review of 68 clinical trials (Tannenbaum et al., 2012), benzodiazepines were consistently associated with both amnestic (involving loss of memory) and non-amnestic cognitive impairment by neuropsychological testing. Given the risks, the use of this class of drugs needs to be carefully assessed for use by older persons, with their use reserved for such indications as seizures or other neurological conditions, alcohol withdrawal, severe generalized anxiety disorder, anesthesia, and end-of-life care.

Evidence from Intervention Studies

Several studies conducted in the past decade have tested interventions aimed at reducing the number of high-risk or harmful medications—as well as the total number of medications—that older adults take with the goal of reducing unnecessary side effects, including cognitive decline. A few studies have focused on reducing intake of medications listed on the Beers Criteria (AGS, 2012; Fick and Semla, 2012; Fick et al., 2003; Ray et al., 1986). A 10-year longitudinal study of older women found that they had a high prevalence of inappropriate medication use and high anticholinergic load; this was especially true in women who developed dementia later in life (Koyama et al., 2013).

A study by Gurwitz and colleagues (2000) found that 68 percent of preventable adverse drug events occurred at the ordering (prescribing) stage of care. Such findings have helped encourage the development of computerized decision support and education as a strategy to help decrease adverse drug events in various settings of care (Alldred et al., 2013). A number of studies have found a statistically significant drop in inappropriate prescribing after the implementation of a computerized decision support system^¹ that used the electronic health record to alert providers to the use of inappropriate medications (Agostini et al., 2007; Mattison et al., 2010; Raebel et al., 2007; Smith et al., 2006; Tamblyn et al., 2003), but none of these studies measured the impact on cognitive outcomes in older adults. Another intervention that has proved successful in discontinuing some medications in older adults is the use of a consultant pharmacist^² alone or in combination with other components (Lukazewski et al., 2014).

A systematic review of the impact of anticholinergic discontinuation on cognitive outcomes in older adults by Salahudeen and colleagues (2014) found positive results from empowerment strategies, such as helping older adults learn about their medications and health status and helping them take the initiative for shared health care decisions to discontinue benzodiazepines. Past efforts at direct-to-consumer advertising by the pharmaceutical industry have been shown to be effective in influencing the public's demand for certain medications (Rosenthal et al., 2002). In another study, the researchers employed a cluster randomized design that assigned community pharmacies to either a treatment group or the control group, with the treatment group being provided with an empowerment process focused on reducing inappropriate benzodiazepine use by the patients. At 6 months, 27 percent of the treatment group had discontinued benzodiazepine use compared with 5 percent of the control group. The empowerment process, which helped older adults gain control and take the initiative to solve the problem, included a detailed patient interview, self-assessment, education, suggestions for non-drug safer substitutions, and the use of peer champions (Tannenbaum et al., 2014).

One over-the-counter antihistamine medication that is commonly used by older adults in the community setting and that worsens cognition is diphenhydramine. Interventions to reduce the use of this medication have been conducted primarily in hospitals. A study by Agostini and colleagues (2007) used a computer-based alert that reminded providers of the side effects of the medication and the dangers of diphenhydramine in older adults and suggested non-drug approaches (such as warm milk and relaxation techniques). This study observed an 18 percent risk reduction in the orders for sedative–hypnotic drugs. A second hospital-based intervention used a computer alert and direct communication between the physician and the pharmacist to achieve a 52 percent reduction in prescribing diphenhydramine (Fosnight et al., 2004). Both of these studies were limited by their prospective, pre–post intervention designs. To date, no research on interventions to limit over-the-counter purchase of diphenhydramine or other related antihistamines by older adults has been published.

Summary

Research has demonstrated that the use of high-risk or potentially inappropriate medications that negatively affect cognition can be effectively reduced or curtailed using techniques such as computerized decision support, consultant pharmacists, and more recently, a direct-to-consumer education approach. However, because of various methodological, clinical, and ethical issues, there has as yet been no research establishing the impact of these initiatives on sustaining or improving cognition. Determining the impact of these medications on cognitive aging will require carefully conducted longitudinal studies. Medication discontinuation interventions need to carefully consider the effects on individuals as well as the various personal preferences of individuals and differing responses to medications and aging. The range of non-drug alternatives is limited by the paucity of strong and individualized evidence for non-drug alternatives in older adults and by the lack of reimbursement for the use of alternatives. Several intervention studies have had moderate methodological limitations, and they have varied widely in how they have measured cognitive function. In the future, studies should use sensitive and validated measures of cognition and should consider issues of dosing, cumulative drug burden effects, effective ways to deliver tailored alternatives, and the impact of medication withdrawal.

MEDICAL CONDITIONS

The evidence on whether treating medical conditions can prevent or reverse cognitive decline and on the impact of medical treatments on long-term cognitive function is complicated. Certain conditions, such as stroke, may result in acute and severe cognitive decline, with the possibility in some cases of regaining some of that cognitive function over time. For stroke and these other conditions, an individual's cognitive trajectory may be determined in large part by the acute event. For other types of conditions, particularly those where prevention and early treatment is the focus (such as diabetes or uncontrolled hypertension), there are many unknowns concerning the extent to which prevention and treatment efforts lead to improvements in cognitive health and how these efforts affect cognitive aging over the life span. For example, reducing the occurrence of strokes will be beneficial to cognitive health; however, much remains to be learned about the effects on cognitive function of treating the individual risk factors for stroke such as hyperlipidemia. Moreover, for some conditions (e.g., hypothyroidism), the benefits of treatment are so compelling—independent of the question of the treatment's effects on cognition—that trials to demonstrate effectiveness on cognition are not needed or ethically justifiable. For these conditions, only observational data are presented, with the assumption that patients with these conditions would be treated and accrue any potential cognitive benefit. For other conditions (e.g., diabetes, obesity) cognitive outcomes are important because they may influence the decisions about the mode or aggressiveness of the treatment. For example, the degree of glycemic or blood pressure control sought for older people with diabetes may need to take into account the adverse consequences of hypoglycemia or hypotension.

Cerebrovascular and Cardiovascular Disease

In the United States, stroke or cerebrovascular accident, which occurs in approximately 2.4 out of every 1,000 persons in the United States (Leys et al., 2005), is a major cause of disability in older adults and the third-leading cause of death in that group (Gorina et al., 2006). There may be considerable overlap between the clinical manifestations of cognitive decline associated with aging and those associated with diagnosed or undiagnosed cardiovascular and cerebrovascular disease (e.g., conditions that may show up as white matter hyperintensities [leukoaraiosis] with magnetic resonance imaging [MRI]). Treatment of cerebrovascular and cardiovascular risk factors might be expected to prevent some of these events and, consequently, the related cognitive declines.

Cognitive decline and dementia are well-recognized sequelae of stroke. For example, one study found dementia in 26 percent of older persons evaluated 3 months after a stroke (Tatemichi et al., 1994). Large strokes can lead to stepwise declines in cognitive functioning, while multiple small strokes may result in only a modestly accelerated course of cognitive decline. While milder degrees of cerebrovascular disease (such as microvascular disease or transient ischemia) have been associated with cognitive decline, the consistency and degree of association has not been clear. In a systematic review of 16 population-based studies (Savva and Stephan, 2010), the occurrence of stroke was found to be associated with a doubling in the risk of incident dementia in the older population. In a systematic review of 30 studies (involving a total of 7,565 patients), the incidence of new dementia following a first-ever stroke was 7.4 percent (95% CI 4.8–10.0) in the first year and 1.7 percent per year (95% CI 1.4–2.0) thereafter (Pendlebury, 2009). Two studies reviewed by Savva and Stephan (2010) suggested that the impact of stroke on the future risk of dementia may be stronger in people with a specific genetic risk factor for Alzheimer's disease (those who are APOE ε4 negative), but the association in three other studies was inconsistent.

The committee supports efforts to improve cardiovascular health in older adults, including through the management of blood pressure, the control of cholesterol, and the maintenance of a healthy body weight (see Chapter 6). Hypoglycemia and hypotension should be avoided because their well-documented harms likely outweigh any potential benefits. The long-term impacts on cognitive aging are largely unknown.

Hypertension

Hypertension is present in approximately 65 percent of people age 60 years and older (Hajjar and Kotchen, 2003) and has been identified in systematic reviews as an important potentially preventable risk factor for cognitive decline and dementia with an increased hazard ratio of between 1.24 and 1.59, depending on the study (Etgen et al., 2011). While the studies vary somewhat in their definition of hypertension, in general, most studies considered a participant to be hypertensive if the average systolic blood pressure was 140 mmHg or higher, the average diastolic blood pressure was 90 mmHg or higher, or the participant was currently receiving antihypertensive medications.

Evidence from Observational Studies

There is robust longitudinal data to support a relationship between blood pressure and cognitive decline (Elias et al., 2012; Etgen et al., 2011) with more consistent associations observed for midlife hypertension; by contrast, late-life hypertension might not be a critical risk factor for cognitive aging (Qiu et al., 2005) More recent studies have also suggested an important role for modification by APOE status (Andrews et al., 2015; Bangen et al., 2013). The impact of hypertension on cognition is likely mediated by a number of mechanisms, including small and large vessel disease, microinfarcts, leukoaraiosis, and changes in cerebral metabolism (Gasecki et al., 2013). Observational studies also indicate that the cognitive function of older adults may possibly benefit from antihypertensive medications (Rouch et al., 2015). Thus, blood pressure control will likely remain an important prevention target in any multifactorial approach to preventing age-related cognitive decline (see Chapter 4C).

Evidence from Intervention Studies

Evidence from blood pressure treatment trials, such as ADVANCE, HYVET-COG, and SCOPE, varies, with some demonstrating a benefit and others reporting no effect on cognition. A recent meta-analysis found that antihypertensive medication had no significant impact on the incidence of Alzheimer's disease, cognitive impairment, or cognitive decline (Chang-Quan et al., 2011). This may reflect differences in the classes of drugs used for hypertension therapy as well as in the timing and duration of treatment (Rouch et al., 2015; Staessen et al., 2011). To gain a better understanding of the effects of blood pressure treatment, the ongoing Systolic Blood Pressure Intervention Trial (SPRINT) will monitor the course of cognitive decline in people undergoing intensive blood pressure control.

Summary

Although the evidence from clinical trials does not demonstrate a clear cognitive benefit from hypertension treatment and the long-term impact on cognitive aging is not known, the benefits for preventing heart attack and stroke, both of which are linked to cognitive decline, are evident. However, in older persons it is particularly important to maintain prudent therapy, with an avoidance of overtreatment, which is associated with adverse cognitive effects as well as falls.

Hyperlipidemia

Hyperlipidemia, or high levels of blood lipids (including triglycerides and cholesterol), is present in approximately 50.8 percent of the older U.S. population (Crawford et al., 2010).

Evidence from Observational Studies

Multiple large population-based observational studies have found that hyperlipidemia, especially hypercholesterolemia, is associated with cognitive decline, with hazard ratio ranging from 1.4 to 1.9 (Etgen et al., 2011). Lipid regulation plays a critical role in neuronal plasticity and survival (Ledesma et al., 2012), and like hypertension, hyperlipidemia may be a stronger risk factor in midlife cognitive decline than in late life (Reynolds et al., 2010; van Vliet, 2012). In addition, some observational studies have found the use of statins (drugs that reduce cholesterol levels) to protect against cognitive impairment (Etgen et al., 2011).

A longitudinal study by Steenland and colleagues (2013) assembled a group—1,244 statin users and 2,363 non-users—and gave them a battery of cognitive tests several times over 3.4 years. They controlled for several potentially confounding conditions, including diabetes, hypertension, and heart disease, and looked for differences in changes in cognitive functioning between the users and non-users of statins. They found that people who had normal cognition at baseline and who used statins had better scores on tests of sustained attention and executive functioning than non-users. Similar benefits for cognition have been observed in large, observational cohorts of older adults without dementia (Bettermann et al., 2012; Solomon et al., 2009).

Evidence from Intervention Studies

In contrast to the above findings, several large randomized controlled trials (RCTs), including the Heart Protection Study and the PROSPER trial (Prospective Study of Pravastatin in the Elderly at Risk), have failed to demonstrate a protective effect of statin treatment on cognitive functioning (McGuinness et al., 2009). A 2009 Cochrane review identified two large RCTs that indicated no benefit of statins on cognitive measures despite their having achieved reductions in serum cholesterol (McGuinness et al., 2009). Similarly, a recent meta-analysis found inconsistent evidence for the effect of statins on cognition among people who were cognitively intact (Richardson et al., 2013). Some drug post-marketing safety reports have suggested that statins might actually impair cognition, which prompted the Food and Drug Administration (FDA) to issue an alert about potential memory loss associated with this class of drugs (FDA, 2012), although a more recent meta-analysis reported no increased risk of adverse cognitive effects related to statin use (Richardson et al., 2013).

Consistent with these studies, a 2010 systematic review of clinical trials of the treatment of cardiovascular risk factors to prevent cognitive decline concluded that there is no apparent cognitive benefit from treating hyperlipidemia and that the treatment of hypertension has only a suggestive effect on cognitive decline (Ligthart et al., 2010).

Summary

Although studies of the benefits of treating hyperlipidemia on cognitive health have had inconsistent results (Plassman et al., 2010), clinical practice guidelines still recommend that high lipid levels be treated because of the beneficial effect on cardiovascular and cerebrovascular diseases (Etgen et al., 2011). Further research will be necessary to identify any specific impact that lipid-lowering drugs have on long-term cognitive functioning.

Diabetes Mellitus and Metabolic Syndrome

Diabetes occurs in about 27 percent of the older U.S. population (CDC, 2011). In addition, metabolic syndrome is estimated to be present in about 42 percent of the population age 70 years and older (Ford et al., 2002). Metabolic syndrome is defined as participants having three or more of the following: abdominal obesity, hypertriglyceridemia, high blood pressure, high fasting glucose, and low high-density lipoproteins. Metabolic syndrome is often unrecognized, and thus its prevalence is underreported (Giannini and Testa, 2003).

Evidence from Observational Studies

Both diabetes and metabolic syndrome have been found to be associated with long-term cognitive decline and an increased risk of dementia in both cross-sectional and long-term observational studies (Plassman et al., 2010; Spauwen et al., 2013; Yaffe et al., 2004). Diabetes is associated with approximately a 1.2-fold increase in risk of cognitive decline, mild cognitive impairment, and dementia (McCrimmon et al., 2012; Plassman et al., 2010). Glycemic control may be a critical factor in this association (Yaffe et al., 2012) and could contribute to both neurodegenerative and vascular damage (Biessels et al., 2014). Because the metabolic syndrome includes both cardiovascular and metabolic components, it may be an especially crucial risk factor for accelerated cognitive aging (Yaffe, 2007).

Evidence from Intervention Studies

People with type 2 diabetes have a higher risk for developing cardiovascular and cerebrovascular disease and may stand to gain more from an aggressive treatment of hypertension and hyperlipidemia. Currently, results from clinical trials are inconsistent as to whether tight glucose control improves cognitive outcomes in type 2 diabetes, and this must be weighed against evidence that too-aggressive efforts to reduce blood sugar levels may increase mortality among high-risk individuals (ACCORD et al., 2008). Moreover, a large RCT conducted in people with type 2 diabetes that examined the effects of an intensive lowering of blood pressure (to systolic target of 120 mmHg) and the treatment of lipids with fenofibrate, found no benefit from either of the two interventions on a wide variety of measures of cognition (including the Mini-Mental State Examination [MMSE], the digit-symbol substitution test, and Stroop, Rey, and auditory verbal learning tests). In preliminary trials, long-acting intranasal insulin has shown promise in improving cognitive function in adults with mild cognitive impairment (MCI) or early Alzheimer's disease (Claxton et al., 2015; Craft et al., 2012). Currently, there is a lack of consistent evidence from clinical trials that tight glucose control improves cognitive outcomes in type 2 diabetes, but there is important evidence that tight control may increase mortality (NHLBI, 2014); furthermore, hypoglycemia may harm cognition (NHLBI, 2014; Yaffe et al., 2012).

Summary

The early recognition and prudent management of diabetes and metabolic syndrome has potential benefit for cognitive health by reducing the risk for cardiovascular and cerebrovascular disease, but much remains to be learned about the direct impact of these factors on cognitive aging. There are specific issues concerning the effects that treatment of these conditions might have on cognitive function that warrant attention. The committee believes that any goals for glycemic control should be consistent with those goals issued by the American Diabetes Association (ADA, 2014).

Obesity

Almost one-third of Americans age 60 years and older are severely overweight or obese, defined as having a body mass index (BMI) of 30 kg/m2 or greater (Wang and Beydoun, 2007).

Evidence from Observational Studies

Although more longitudinal studies are needed (Plassman et al., 2010), evidence is emerging to support the existence of obesity-related brain changes and dysfunction in cognition (Sellbom and Gunstad, 2012). While the effects of obesity may be mediated through other pathways, such as through the well-described effects of diabetes or metabolic syndrome (i.e., inflammation, insulin resistance, endothelial dysfunction, and microvascular disease) and through the complications of obesity, such as obstructive sleep apnea, obesity may also increase risk of cognitive aging directly through the presence of excess adipose tissue and the secretion of inflammatory proteins such as leptin, which have been linked to cognitive impairment and decline (Gustafson, 2012; Holden et al., 2009; Zeki Al Hazzouri et al., 2013). A meta-analysis also suggests that the effects of BMI on cognition may differ between midlife and late life (Anstey et al., 2011).

Evidence from Intervention Studies

A randomized trial among middle-aged overweight or obese individuals that compared an energy-restricted low-calorie diet with a conventional low-fat diet with no change in calorie intake found a time-effect improvement on working memory in both groups at 1 year but no differences between groups; these diets had no effect on speed of mental processing (Brinkworth et al., 2009).

A recent RCT among obese older individuals compared the effects of four regimens—a diet aimed at reducing caloric intake by 500–750 kcal/day below requirements, exercise using a multicomponent progressive training program, both diet and exercise, and neither—and found that those assigned to diet alone performed better than the control group on the modified-MMSE but not as well as those assigned to exercise alone; the combination of diet and exercise was no more effective than exercise alone. The effects of diet alone on other measures, including word-list fluency and the Trail Making Test, Parts A and B, were not significant (Napoli et al., 2014). A 2011 meta-analysis concluded that weight loss had inconsistent effects on memory and modest beneficial effects on attention/executive function, generally in obese subjects (Siervo et al., 2011). Among obese middle-aged persons, bariatric surgery resulted in improvement on a verbal list learning test compared to obese controls when assessed 24 months after surgery (Alosco et al., 2014).

Summary

While the exact mechanism by which obesity contributes to cognitive decline remains unclear, given its prevalence and serious associated complications, morbid obesity may act on mediating pathways (e.g., through diabetes and hypertension) to produce long-term cognitive impairment (Etgen et al., 2011; Plassman et al., 2010). The studies reviewed here are those focusing on weight loss itself rather than any particular diet; specific diets are addressed in Chapter 4A. Further research is needed on the effect of weight loss and bariatric surgery on cognitive outcomes.

Delirium and Hospitalization

Nearly every individual will experience at least one acute medical illness, surgery, or hospitalization, and nearly one-third of the older U.S. population is hospitalized each year (HHS, 2013). Delirium, an acute disorder of attention and confusion, is the most common complication of acute illness and hospitalization for older people in the United States, occurring in an estimated 2.6 million individuals per year (HHS, 2011). Up to 50 percent of all Americans age 65 years and older will develop delirium during the course of a hospitalization, with the associated increased risks of institutionalization and death leading to health care costs that exceed $160 billion per year (Inouye et al., 2014).

Evidence from Observational Studies

Delirium Although common, delirium is preventable in some 30 to 50 percent of cases (Inouye et al., 2014), and every effort should be made to prevent it, as it significantly increases a person's risk for long-term cognitive decline and dementia. A systematic review and meta-analysis found two studies involving 241 patients demonstrating an increased odds ratio for incident dementia following delirium (Witlox et al., 2010). Another study of 225 cardiac surgery patients age 60 years and older demonstrated that delirium is independently associated with cognitive decline at 1 year post-surgery; the time pattern of cognitive functioning showed an initially steep decline followed by improvement but with residual impairment (Saczynski et al., 2012). A study of 821 intensive care unit (ICU) patients found that a longer duration of delirium was independently associated with worse global cognitive function and executive function at 3 and 12 months follow-up (Pandharipande et al., 2013). The adverse impact of delirium on cognitive trajectory is magnified among patients with underlying dementia (Fong et al., 2009; Gross et al., 2012).

A recent comprehensive review found six prospective studies document delirium's association with long-term cognitive decline after hospitalization, whether a follow-up occurred soon (2 months) or a longer time (12 months) afterward (Mathews et al., 2014). Some of the studies in this review lacked baseline (pre-hospitalization) cognitive testing, however. The disparate reasons for hospitalization (acute illness, surgery, intensive care, palliative care) may have different prognostic implications for cognitive decline.

Hospitalization Regardless of admitting diagnosis, hospitalization is increasingly recognized as a major stressor for older adults and an important independent contributor to cognitive and functional decline (Krumholz, 2013). A study of 1,870 community-dwelling older adults demonstrated an independent 2.4-fold increase in the rate of cognitive decline following a first hospitalization, even after controlling for demographic factors, illness severity, and pre-hospital cognitive trajectory (Wilson et al., 2012). The impact of hospitalization was greatest on short-term memory and executive functioning. Another study of 2,929 patients admitted to a hospital or ICU who were followed afterward for a median of 4 years found an increased rate of cognitive decline following either hospitalization or ICU stay and an increased hazard ratio for incident dementia at follow-up of 1.4 (95% CI 1.1–1.7) and 2.3 (95% CI 0.9–5.7) after the hospitalization and ICU stay, respectively (Ehlenbach et al., 2010).

Mathews and colleagues (2014) found six studies (five prospective and one retrospective) showing that acute hospitalization was associated with long-term cognitive decline, but several of these studies did not include formal preadmission cognitive testing. Despite those studies' limited and heterogeneous nature, a consistent picture is emerging that points to the important contributions of delirium, acute illness, and hospitalization to long-term cognitive decline and possibly dementia.

Evidence from Intervention Studies

Catalyzed by the strong observational evidence summarized above, delirium prevention has emerged as a priority in the prevention of cognitive decline following major illness, hospitalization, or surgery. Authoritative guidelines and systematic reviews recommend multicomponent, non-pharmacologic intervention strategies targeted toward patients with delirium risk factors and implemented by skilled interdisciplinary teams (Greer et al., 2011; O'Mahony et al., 2011). Two recent systematic reviews and meta-analyses (AGS Expert Panel 2014; Hshieh et al., 2014) of 10 and 14 intervention studies, respectively, have documented the effectiveness of these approaches. The interventions were largely based on the Hospital Elder Life Program (the original model of which has been widely disseminated with consistent effectiveness) (Inouye, 2000; Inouye et al., 1999, 2006; Rubin et al., 2011; Zaubler et al., 2013) and included the following approaches: cognitive orientation, sleep enhancement (i.e., non-pharmacologic sleep protocol and sleep hygiene), early mobility and/or physical rehabilitation, adaptations for visual and hearing impairment, nutrition and fluid replenishment, pain management, appropriate medication usage, adequate oxygenation, and prevention of constipation (HELP, 2014). Rounds by an interdisciplinary team and associated strategies to assure adherence to recommended interventions were important to the protocol's effectiveness. At least five of the studies demonstrated a “dose–response” relationship between the level of adherence and the intervention's effectiveness (Holt et al., 2013; Inouye et al., 1999, 2000, 2003; Vidan et al., 2009).

In addition to the prevention of incident delirium, these studies demonstrated consistent beneficial impact for the following outcomes: cognitive decline, functional decline, length of hospital stay, nursing home placement, falls, and health care costs. In a meta-analysis of 14 studies, 11 studies demonstrated significant reductions in delirium duration and incidence (odds ratio: 0.47; 95% CI 0.38–0.58) (Hshieh et al., 2014).

Summary

Because one-third of older Americans will be hospitalized each year for acute illness or surgery, putting them at increased risk of delirium and subsequent cognitive decline in addition to them facing the associated higher morbidity, mortality, and health care costs, the committee believes that the implementation of proven cost-effective multicomponent non-pharmacologic delirium-prevention strategies is vital. These regimens should be implemented by interdisciplinary teams and targeted to patients with demonstrated risk factors, who should have cognitive assessments either before or immediately after hospital admission or surgery (HELP, 2014). More needs to be learned about the long-term impacts of delirium on cognitive aging.

Major Surgery and General Anesthesia

The association of major surgery and general anesthesia with cognitive decline has gained recent widespread attention. Previous epidemiologic studies have documented a persistent cognitive decline following major surgery, yet it has been assumed that this decline may be due more to patients' pre-operative trajectories than to the effects of the surgery or anesthesia (Selnes et al., 2012). Some of the older studies have lacked presurgical baseline cognitive trajectories and have inadequately controlled for potential confounding variables. Thus, it has been difficult to determine whether any cognitive impairment arising after surgery is attributable to the surgery or anesthesia (Avidan and Evers, 2011; Rudolph et al., 2010; van Dijk et al., 2000) rather than to associated comorbidity, delirium, or stressors related to the hospitalization. Furthermore, previous studies have failed to demonstrate any difference in cognitive outcomes between patients who received general and regional anesthesia (Newman et al., 2007). This is an important area of research that could assist in the exploration of the long-term impacts on cognitive aging.

OTHER MEDICAL CONDITIONS

A number of other medical conditions may be associated with cognitive changes and decline. Because the prevention and treatment of each of these conditions have been the subjects of extensive research, albeit not focused on cognitive outcomes, this report does not summarize the intervention literature. For each condition, little is known about how the medical condition might or might not affect cognitive aging.

Thyroid Disorders

Both hypo- and hyperthyroidism have been long identified as major reversible causes of cognitive decline and are screened for in many cases of cognitive impairment. However, the contribution to impaired cognition by subclinical thyroid disease, defined as abnormal levels of thyroid-stimulating hormone (TSH) in the face of normal levels of thyroxine (T4) and triiodothyronine (T3), is less clear. The presence of subclinical thyroid disease increases with age, with rates from 7 to 25 percent in persons age 60 years and older (Ceresini et al., 2009; Etgen et al., 2011).

In a recent systematic review of 11 studies, including six population-based prospective studies and five cross-sectional studies, six of the studies supported the association between subclinical hypothyroidism and cognitive impairment (Annerbo and Lokk, 2013). The confounding influence of acute illness, comorbidity, and medications—which can substantially affect TSH, T4, and T3 levels—were not controlled for in many studies (Roberts et al., 2006). Given the inconsistent association and the small number of studies, subclinical thyroid disease is not considered to be a major risk factor for cognitive decline at this time; however, it remains of interest for future investigation and the possible development of preventive interventions.

Chronic Kidney Disease

Chronic kidney disease, defined as having kidney damage or a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m², is a highly prevalent condition, present in more than 45 percent of adults age 70 years and older (Anand et al., 2014). Emerging evidence indicates that chronic kidney disease is an independent contributor to decline in cognitive function. An estimated 70 percent of hemodialysis patients 55 years of age and older will have moderate to severe cognitive impairment (Elias et al., 2013); however, even milder degrees of renal impairment are associated with cognitive impairment.

A recent systematic review and meta-analysis involving seven cross-sectional and 10 prospective studies with more than 54,000 participants who were pre-dialysis but with mild to severe renal impairment demonstrated an increased relative risk for cognitive decline of 1.65 (95% CI 1.32–2.05) and 1.39 (95% CI 1.15–1.68), respectively, even after adjustment for confounding factors (Etgen et al., 2012). Importantly, the reviewers found a dose–response relationship with the more severe degrees of renal failure (GFR >60) creating a greater risk for cognitive decline than did milder degrees of renal impairment (GFR of 45 to 60 or GFR <45). There are a number of possible mechanisms that could potentially explain the association of chronic kidney disease with cognitive decline, including vascular risk factors (hypertension, diabetes, hyperlipidemia, cardiovascular disease), cerebral ischemia/stroke, elevated homocysteine, hypercoagulability, oxidative stress, inflammation, anemia, metabolic derangements (hyperparathyroidism, malnutrition, hypoalbuminemia), polypharmacy, depression, and sleep disorders (Elias et al., 2013; Etgen et al., 2012). Many of these represent important potential targets for secondary prevention of cognitive decline among people with chronic kidney disease.

Cancer

Approximately 9 million persons, or 3 percent of the U.S. population, are cancer survivors (Anderson-Hanley et al., 2003). Cognitive functioning among cancer patients may be influenced by the malignancy itself as well as by the effects of the associated treatments, including chemotherapy, surgery, radiation, hormonal therapy, and biologics, alone or in combination.

A meta-analysis of 30 studies involving a total of 838 patients examined at 1 month to several years following cancer treatment showed significant decreases in neuropsychological testing scores due to the above causes, with the largest impact on the areas of executive functioning and verbal memory (Anderson-Hanley et al., 2003). A twin study of 702 cancer survivors demonstrated that the twin who had cancer was significantly more likely (relative risk [RR] 2.10, 95% CI 1.36–3.24) to develop cognitive decline than the co-twin (Heflin et al., 2005). In addition, the risk of dementia was doubled, although it did not reach statistical significance.

While these studies are suggestive, the evidence that cancer and its treatment leads to cognitive impairment and dementia remains equivocal, particularly in light of potential confounding by vascular disease, other comorbidities, and their treatment. Moreover, few older people are included in most cancer trials and follow-up studies. In a systematic review of 88 articles (Bial et al., 2006), no conclusions about cognition could be reached because of the small and heterogeneous nature of the studies, along with the shortage of older persons included. This important gap will need to be addressed.

Depression

Depression is a common mental health problem across the life span, with one in five U.S. adults experiencing at least one depressive episode during a lifetime (Byers and Yaffe, 2011). The prevalence of depression ranges from 7 to 36 percent in older adult populations (Crocco et al., 2010).

Midlife depression has been consistently associated with about a twofold increased risk for subsequent cognitive decline or dementia (Byers and Yaffe, 2011). While a similar association has been demonstrated for late-life depression, caution is warranted in interpreting these studies since dementia has a long prodromal phase and can coexist with cognitive decline or dementia; establishing whether depression represents a cause, an effect, a manifestation of a shared mechanism, or a chance co-occurrence can be challenging. Nonetheless, a recent systematic review supported a strong relationship between late-life depression and subsequent dementia, with the strongest risk for vascular dementia.

A meta-analysis of 23 population-based studies examining late-life depression and involving more than 49,000 people demonstrated a significantly increased risk for all-cause dementia (RR 1.85, 95% CI 1.67–2.04), Alzheimer's disease (RR 1.65, 95% CI 1.42–1.92), and vascular dementia (RR 2.52, 95% CI 1.77–3.59) (Diniz et al., 2013). An earlier review of 13 studies involving more than 32,000 people found relative risks of 1.5 to 6.0 for cognitive decline or dementia (Plassman et al., 2010).

Potential mechanisms by which depression may contribute to cognitive decline and dementia include alterations in the glucocorticoid–stress hormone pathway and hippocampal atrophy, inflammatory changes, vascular disease with involvement of the frontal-striatal pathway, and accelerated deposition of beta-amyloid (Byers and Yaffe, 2011; Crocco et al., 2010). While the exact relationship between depression and cognition awaits clarification, given depression's prevalence and potential implications, its prevention and intervention should be an important goal in enhancing functioning and quality of life for older adults.

TRAUMATIC BRAIN INJURY

Brain trauma can occur at any age, and it varies dramatically in its severity, comorbid effects, and clinical outcomes. It may occur multiple times to the same individual, such as from repeated falls, from recurring concussions in sports participation, from military service, or from multiple injuries associated with chronic substance abuse. Falls are the leading cause of brain trauma among older adults. Traumatic brain injury (TBI) is often divided into mild and severe categories; while criteria for these categories have been promulgated and are useful, they require additional research and validation (Arciniegas and Silver, 2001).

Severe TBI usually is associated with some period of coma, hospitalization, and prolonged rehabilitation. There is usually gross anatomic brain damage (e.g., a penetrating wound, hemorrhage, or displaced or destroyed brain tissue). Persistent pathological problems may emerge, including hydrocephalus, vascular compromise, and fibrosis. These sequelae of brain injury may lead to long-term cognitive impairments, which cause substantial functional disability (Vincent et al., 2014). The trajectories after severe TBI need to be better understood, including determining risk factors for improvement and adverse effects on later life cognitive function.

Mild TBI may be associated with concussion, but unconsciousness is likely to be brief, and mild TBI less often requires hospitalization or long-term rehabilitation. Remaining TBI symptoms, the so-called post-concussion syndrome—irritability, headache, fatigue, and dizziness—may persist for days or weeks (Eisenberg et al., 2014) and can be frustrating to patients and clinicians and may impede conventional cognitive evaluation. Concerning single or multiple mild TBI episodes that appear to resolve to clinical “normalcy,” the central questions are whether they lead to later increases in the risk of cognitive decrements, and if so, what the range of severity is and how those at greater risk can be identified.

Many but not all studies find TBI to be associated with cognitive decrements in later life compared to control groups, as determined both by cognitive testing and by brain anatomic and physiological characteristics (Ashman et al., 2008; Broglio et al., 2012; Konrad et al., 2011; Moretti et al., 2012). In addition, an older age at the time of the TBI and a greater interval between the injury and the evaluation have been independently associated with worse cognitive outcomes (Ponsford and Schonberger, 2010; Ponsford et al., 2008; Senathi-Raja et al., 2010). Some follow-up studies of 30 years or more (Isoniemi et al., 2006) have detected differences in some elements of cognitive performance between people with past TBI and control groups (Barnes et al., 2014). However, one systematic review found chronic cognitive impairment in mild TBI patients to have occurred only among those who had complications in their clinical course (Godbolt et al., 2014). TBI in general has been associated with increased risk of dementia among U.S. military veterans (Barnes et al., 2014).

The evidence for the long-term role of mild TBI in chronic cognitive impairment is mixed and far from definitive. This is a challenging area to study because of differences in the types and severity of injury, the selection of appropriate control groups, the need for lengthy follow-up, the presence of comorbidities, and the existence of many alternative potential causes of cognitive change. Definitions of cognitive impairment also vary. Although long-term studies are difficult to perform, they are critical to evaluating this exposure and are particularly important because they have the potential to strengthen public health efforts aimed at TBI prevention.

Summary for Medical Conditions

The evidence for the contributions of the medical conditions examined in this section on the cognitive aging process is mounting, yet the impact and mechanisms often remain unclear. In addition, targeted intervention strategies to prevent cognitive decline associated with these conditions have not been well examined. This is a priority for future research.

HEARING AND VISION LOSS

Alterations in sensation and perception with aging can have substantial effects on daily function, and ongoing research is investigating the role of hearing and vision loss in cognitive performance. Vision loss and low visual acuity, both of which are common among older adults, have been associated with decreased cognitive function (Clemons et al., 2006), but the precise effect depends on the type of eye disease (Keller et al., 1999; Tay et al., 2006). Age-related changes in vision include: declines in visual acuity and in the range of visual accommodation, loss of contrast sensitivity, decreases in abilities to visually adapt to darkness, declines in color sensitivity, and heightened sensitivity to glare (Czaja and Lee, 2003).

Some causes of visual impairment, such as cataracts or retinitis, are related to pathology in eye structures; others may be related to brain diseases, such as neurodegenerative conditions, where there are underlying problems in visual-spatial perception. The mechanisms by which declining visual acuity relates to cognitive aging are not always clear, but they may include decreased social activity and increased risk of falls, possibly leading to head injury (Wood et al., 2011). Some types of visual impairment, such as decreased near vision, may be risk factors for cognitive impairment (Reyes-Ortiz et al., 2005). Also, because both cognitive changes and visual loss emerge slowly, it can be difficult to determine which came first. Nonetheless, there is reasonably strong evidence that visual impairment is a risk factor for cognitive change, even after controlling for mental status and comorbidity (Clemons et al., 2006; Lin et al., 2004; Reyes-Ortiz et al., 2005).

Age-related losses in hearing include a loss of sensitivity for pure tones, especially high-frequency tones; difficulty understanding speech, especially if the speech is distorted or embedded in noise; problems related to localizing sounds and binaural hearing; and increased sensitivity to loudness (Schieber and Baldwin, 1996). While severe hearing loss can make it difficult to assess cognitive function, this sensory impairment has been identified in several studies as a risk factor for cognitive decline, incident dementia, and severity of cognitive dysfunction (Lin et al., 2011, 2013; Uhlmann et al., 1989). Studies of combined hearing and visual impairment have also found an association with cognitive aging (Lin et al., 2004). Preexisting neurodegenerative diseases may preclude accurate auditory testing.

Irrespective of the relationship between vision or auditory impairment and cognitive function, improving and maximizing sensory function is important to quality of life and general function and mobility for older adults, and it should be addressed (Genther et al., 2013; Lin et al., 2004). These changes can affect interactions with the health care system as well. For example, age-related changes in vision might make it difficult for an older person to read labels on a medication bottle, which may in turn affect the proper use of prescription drugs. Similarly, age-related changes in hearing might make it difficult for an older adult to engage in a conversation or to understand oral instructions, particularly when speech is rapid.

SLEEP

Evidence from Observational Studies

Epidemiological studies of self-reported sleep quality have generally shown an association among poorer cognitive function, insomnia symptoms, and poor sleep quality (Fortier-Brochu et al., 2012; Schmutte et al., 2007), although the results of studies evaluating cognitive impairment and sleep patterns have been mixed. Some studies have shown a roughly two-to four-fold increase in the risk of cognitive decline or impairment among those who reported sleep disturbances (Elwood et al., 2011; Jelicic et al., 2002; Potvin et al., 2012; Sterniczuk et al., 2013), while others have found no association (Foley et al., 2001; Jaussent et al., 2012; Merlino et al., 2010; Tworoger et al., 2006). Differing results across studies using self-reports about sleep patterns may be due in part to the heterogeneity of the study methods and design. The majority of studies using objective measures to determine sleep quality have supported a greater risk of cognitive decline, impairment, and Alzheimer's disease being associated with disturbed sleep, as measured by non-invasive actigraphy, including associated longer time needed to fall asleep, increased sleep fragmentation, and waking after sleep onset (Blackwell et al., 2006, 2011; Lim et al., 2013a). Furthermore, better sleep consolidation has been shown to reduce the incidence of cognitive decline (Lim et al., 2013b). Observational studies have suggested that there may be a U-shaped association between sleep duration and cognition, with worse cognitive outcomes associated with both long and short sleep durations compared to more intermediate sleep lengths of 7 to 8 hours (Yaffe et al., 2014).

Disordered breathing during sleep, typically involving apneas (the cessation of breathing) and hypopneas (reduced or shallow breathing), also has been associated with impairments in cognitive function. In some cross-sectional studies, indicators of sleep disordered breathing have been associated with worse cognition (Beebe et al., 2003; Spira et al., 2008), but not all studies have found this (Blackwell et al., 2011; Foley et al., 2003). Prospective studies have shown older adults with sleep disordered breathing have greater cognitive decline (Cohen-Zion et al., 2004) and an increased risk of MCI or dementia than those without disordered breathing during sleep (Yaffe et al., 2011). Taken together, these results suggest that improving sleep may prove beneficial for cognitive outcomes among older adults.

Evidence from Intervention Studies

A number of treatments have been shown to be effective in improving sleep among older adults, but few trials have evaluated the cognitive benefits of these treatments. A small study among older adults with insomnia showed improvements in both sleep quality (falling asleep sooner and staying asleep) and cognitive performance after 8 weeks of a computerized cognitive training program (Haimov and Shatil, 2013). Exercise, primarily aerobic, has also shown potential for benefiting sleep and well-being among older adults with and without insomnia (Benloucif et al., 2004; Montgomery and Dennis, 2002; Reid et al., 2010), but further study is needed to evaluate effects on cognitive aging.

Promising results have also been demonstrated for the use of light therapy to ameliorate sleep and circadian rhythm disturbances in people with Alzheimer's disease and other dementias, although the cognitive benefits have not yet been determined (Hanford and Figueiro, 2013; McCurry et al., 2011; Salami et al., 2011). Several small trials have shown that acetylcholinesterase inhibitors may improve sleep and cognitive outcomes among both healthy adults and those with Alzheimer's disease (Ancoli-Israel et al., 2005; Cooke et al., 2006; Hornung et al., 2009; Mizuno et al., 2004; Moraes Wdos et al., 2006; Schliebs and Arendt, 2006); however, the benefits must be weighed against the potential side effects (Inglis, 2002), and larger prospective trials are needed to determine long-term outcomes.

Sleep disordered breathing is a promising modifiable risk factor for improving cognitive outcomes; however, the timing and duration of its treatment as well as the optimal treatment population are still unclear. A meta-analysis of 13 treatment studies found improvements in attention, but most trials were short-term and underpowered (a mean sample size of 54) (Kylstra et al., 2013). In one small 3-month study of sleep apnea patients, continuous positive airway pressure (CPAP) treatment resulted in improved cognitive function in several domains that corresponded to gray matter volume increases in hippocampal and frontal regions (Canessa et al., 2011). Another small study found that compliant use of CPAP for 3 months was associated with broad improvements in cognitive functioning, such as in attention, psychomotor speed, executive functioning, and nonverbal delayed recall (Aloia et al., 2003). Results from the recent Apnea Positive Pressure Long-term Efficacy Study (APPLES) trial showed improvements in executive function among patients with severe obstructive sleep apnea following CPAP therapy over 2 and 6 months, but no improvement on tests of attention, psychomotor function, or memory (Kushida et al., 2012). Another study evaluating functional MRI changes in 17 participants undergoing 2 months of CPAP treatment suggested that treatment improves cognitive function but that the potential to reverse neuronal damage may be limited (Prilipko et al., 2012).

Some promise has been shown for certain drugs, such as donepezil and fluticasone, in treating obstructive sleep apnea and improving cognitive outcomes; however, the evidence is currently insufficient to recommend the use of drug therapy in treating obstructive sleep apnea, and additional studies among larger populations with long durations of follow-up are needed (Mason et al., 2013).

Summary

In aggregate, observational and intervention studies suggest that insomnia and sleep disorders may impair cognitive function in older adults and that their treatment has the potential to ameliorate this effect. The long-term effects on cognitive aging are unknown. Most intervention trials have been small and short-term, and additional studies among larger populations and longer follow-up are needed (Mason et al., 2013). The treatment of sleep disordered breathing has particular promise for improving cognitive outcomes. The mainstay of current treatment for obstructive sleep apnea consists of non-pharmacologic approaches, including CPAP and weight reduction.

GENETIC FACTORS: APOE STATUS

Advances in genetics and molecular biology have prompted substantial exploration of a possible genetic basis for age-related cognitive impairment. Most of these “risk factor” investigations have attempted to identify genetic predictors and correlates of Alzheimer's disease and other neurodegenerative dementias. Currently, interest in possible genetic impacts on other late-life cognitive changes, both negative and positive, is increasing. To date, the gene (and surrounding genetic regions) found to be most closely related to decreased cognitive function in later life secondary to Alzheimer's disease is the APOE ε4 allele (Davies et al., 2014). This has been established in many studies and summarized in a meta-analysis by Small and colleagues (2004). However, while this finding is important for use in clinical prediction or in evaluating early or familial cognitive syndromes, the committee is not aware of any U.S. national expert group that has recommended routine APOE ε4 screening in asymptomatic adults. Furthermore, evidence suggests that the APOE ε4 allele has different cognitive effects at different ages (Qiu et al., 2004).

It is difficult to assess the significance of other genes and related genetic markers that have been identified in diverse studies related to cognitive maintenance (Payton, 2009). The studies have several methodological features that impede comparison, including varied study populations, the strength of the association is usually small, findings vary in different study populations, studies often fail to consider relevant comorbid conditions, different studies find associations with different cognitive outcomes, and biological interactions exist among implicated genes (Adamczuk et al., 2012).

A recent meta-analysis reported on more than 20 genetic loci that have demonstrated modest but significant effects on dementia risk (Bertram and Tanzi, 2008). In at least one recent genome-wide association study, yet another genetic location (on chromosome 11) appeared to be associated with cognitive maintenance in older adults (Yokoyama et al., 2014). Other such genetic factors may exist. Thus, new and potentially important genetic variants continue to be identified that may turn out to be relevant to maintaining late-life cognitive performance (Sweet et al., 2012; Yokoyama et al., 2014), and other genetic factors, such as epigenetic determinants, may also be operative (Akbarian et al., 2013).

Summary

Overall, it appears that while genetic forces must be ultimately important in cognitive aging, the research is at an early stage, the particular genes and related mechanisms have not been identified, and the research quest continues. At present, the exact role of genetic factors in cognitive maintenance and decline remains unclear, with little reason at this time to perform genetic testing among older persons in the general population either to predict cognitive risk or to guide treatment decisions. Further research in this area is clearly needed.

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Footnotes

1: Computerized decision support (CDS) interventions can encompass a variety of levels of support, but most CDS interventions for medication use will alert the provider before the medication is prescribed (when the provider attempts to enter or prescribe the medication) and will offer a suggested drug alternative, a behavioral or non-drug approach, or both a drug and a non-drug alternative.
2: Consultant pharmacists consult with other health care professionals, patients, and caregivers about high-risk drugs, dosage issues, side effects, cumulative drug burden and drug–drug interactions to ensure appropriate use of medication. Consultant pharmacists practice in a wide variety of settings, including subacute care and assisted living facilities, psychiatric hospitals, hospice programs, and in home- and community-based care (ASCP, 2014).

Tables

TABLE 4B-1American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Due to Drug-Disease or Drug-Syndrome Interaction That May Exacerbate the Disease or Syndrome

Disease or Syndrome	Drug	Rationale	Recommendation, Quality of Evidence, and Strength of Recommendation
Delirium	All tricyclic antidepressants Anticholinergics (see Table 4B-2) Benzodiazepines Chlorpromazine Corticosteroids H₂-receptor antagonists Meperidine Sedative hypnotics Thioridazine	Avoid in older adults with or at high risk of delirium because of inducing or worsening delirium in older adults; if discontinuing drugs used chronically, taper to avoid withdrawal symptoms	Recommendation: Avoid Quality of Evidence: Moderate Strength of Recommendation: Strong
Dementia and Cognitive Impairment	Anticholinergics (see Table 4B-2) Benzodiazepines H₂-receptor antagonists Zolpidem Antipsychotics, chronic and as-needed use	Avoid because of adverse central nervous system effects. Avoid antipsychotics for behavioral problems of dementia unless nonpharmacological options have failed, and patient is a threat to themselves or others. Antipsychotics are associated with an increased risk of cerebrovascular accident (stroke) and mortality in persons with dementia	Recommendation: Avoid Quality of Evidence: High Strength of Recommendation: Strong

: SOURCE: AGS, 2012. Reprinted with permission of John Wiley & Sons, Inc.

TABLE 4B-2Drugs with Strong Anticholinergic Properties

Antihistamines	Antidepressants	Antimuscarinics (urinary incontinence)	Antiparkinson Agents	Antipsychotics	Antispasmodics	Skeletal Muscle Relaxants
Brompheniramine Carbinoxamine Chlorpheniramine Clemastine Cyproheptadine Dimenhydrinate Diphenhydramine Hydroxyzine Loratadine Meclizine	Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Nortriptyline Trimipramine	Darifenacin Fesoterodine Flavoxate Oxybutynin Solifenacin Tolterodine Trospium	Benztropine Trihexyphenidyl	Chlorpromazine Clozapine Fluphenazine Loxapine Olanzapine Perphenazine Pimozide Prochlorperazine Promethazine Thioridazine Thiothixene Trifluoperazine	Atropine products Belladonna alkaloids Dicvclomine Homatropine Hyoscyamine products Propantheline Scopolamine	Carisoprodol Cyclobenzaprine Orphenadrine Tizanidine

: SOURCE: AGS, 2012. Reprinted with permission of John Wiley & Sons, Inc.

Bookshelf ID: NBK316194

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