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Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.1 An estimated one-third of AD cases can be attributed to modifiable risk factors.2 Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.
Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.3 Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”
Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.4
Physical exercise
Twenty-one percent of AD cases in the United States are attributable to physical inactivity.5 In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).6
The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.7 Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al8 categorized leisure-time activities into 3 types:
- light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
- moderate (bicycling, swimming, hiking, playing tennis)
- vigorous (aerobic dancing, jogging, playing handball).
These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).8
In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).9 Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).10
Continue to: From a pathophysiological standpoint...
From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.11 This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.12
Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.13 These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week14 (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).15
Mental activity
Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.5 Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.16 Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.17 Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.18 The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.19
In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.20 Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.21
Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.22 Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.23
Continue to: Physicians should encourage their patients...
Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).
Social activity
Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.24 Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).25 In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).26
A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.27 Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.28
Meditation/spiritual activity
Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.29 Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neurodegenerative processes of AD.30 In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).31 By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.
Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.32 Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control33 and functional connectivity in brain regions implicated in executive functioning,34 as well as by modulating inflammatory processes implicated in AD.35 Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.36
Continue to: Kirtan Kriya is a medication technique...
Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.37 However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).38
Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).39
Diet
In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.40 The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.41 A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.42 In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.43,44
Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.45 In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.46 Scarmeas et al8 found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neurocognitive improvement in patients with hypertension.47 Both the Mediterranean and DASH diets have been associated with better cognitive function48 and slower cognitive decline.49 Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.50
Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.51
Continue to: Curcumin, which is derived from...
Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.52 However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.53 A longer follow-up is required to determine if curcumin can delay or prevent AD.
Alcohol
The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).54 Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).55 Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.55
The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.56 According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),57 moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).58
In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).59 In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.60 Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.54 However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.61 Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).61
Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.62 Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.13
Continue to: Coffee/tea
Coffee/tea
Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.66 Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.67 These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine,
An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.69 Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.70
Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.71 In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.72 More studies are needed to confirm its potential preventative role in AD.
Which lifestyle change is the most important?
Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.73
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities74:
- a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
- regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
- cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
- optimal management of cardiovascular risk factors.
Continue to: This multi-domain approach...
This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).
Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multidimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).75
On a practical basis, Desai et al13 have proposed a checklist (Table 213) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.
Bottom Line
Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.
Related Resources
- Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
- Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
- Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.
Drug Brand Name
Curcumin • Theracurmin
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67. Arendash GW, Cao C. Caffeine and coffee as therapeutics against Alzheimer’s disease. J Alzheimers Dis. 2010;20 (Suppl 1):S117-S126.
68. Eskelinen MH, Ngandu T, Tuomilehto J, et al. Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J Alzheimers Dis. 2009;16(1):85-91.
69. Solfrizzi V, Panza F, Imbimbo BP, et al. Coffee consumption habits and the risk of mild cognitive impairment: the Italian longitudinal study on aging. J Alzheimers Dis. 2015;47(4):889-899.
70. Vittoria Mattioli. Beverages of daily life: impact of caffeine on atrial fibrillation. J Atr Fibrillation. 2014;7(2):1133.
71. Chacko SM, Thambi PT, Kuttan R, et al. Beneficial effects of green tea: a literature review. Chin Med. 2010;5:13.
72. Noguchi-Shinohara M, Yuki S, Dohmoto C, et al. Consumption of green tea, but not black tea or coffee, is associated with reduced risk of cognitive decline. PLoS One. 2014;9(5):e96013. doi: 10.1371/journal.pone.0096013.
73. Schneider N, Yvon C. A review of multidomain interventions to support healthy cognitive ageing. J Nutr Health Aging. 2013;17(3):252-257.
74. Ngandu T, Lehitsalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255-2263.
75. U.S. National Library of Medicing. ClinicalTrials.gov. U.S. study to protect brain health through lifestyle intervention to reduce risk (POINTER). https://clinicaltrials.gov/ct2/show/NCT03688126?term=pointer&cond=Alzheimer+Disease&rank=1. Published September 28, 2018. Accessed November 3, 2018.
Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.1 An estimated one-third of AD cases can be attributed to modifiable risk factors.2 Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.
Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.3 Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”
Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.4
Physical exercise
Twenty-one percent of AD cases in the United States are attributable to physical inactivity.5 In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).6
The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.7 Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al8 categorized leisure-time activities into 3 types:
- light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
- moderate (bicycling, swimming, hiking, playing tennis)
- vigorous (aerobic dancing, jogging, playing handball).
These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).8
In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).9 Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).10
Continue to: From a pathophysiological standpoint...
From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.11 This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.12
Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.13 These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week14 (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).15
Mental activity
Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.5 Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.16 Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.17 Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.18 The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.19
In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.20 Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.21
Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.22 Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.23
Continue to: Physicians should encourage their patients...
Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).
Social activity
Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.24 Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).25 In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).26
A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.27 Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.28
Meditation/spiritual activity
Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.29 Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neurodegenerative processes of AD.30 In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).31 By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.
Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.32 Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control33 and functional connectivity in brain regions implicated in executive functioning,34 as well as by modulating inflammatory processes implicated in AD.35 Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.36
Continue to: Kirtan Kriya is a medication technique...
Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.37 However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).38
Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).39
Diet
In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.40 The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.41 A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.42 In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.43,44
Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.45 In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.46 Scarmeas et al8 found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neurocognitive improvement in patients with hypertension.47 Both the Mediterranean and DASH diets have been associated with better cognitive function48 and slower cognitive decline.49 Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.50
Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.51
Continue to: Curcumin, which is derived from...
Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.52 However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.53 A longer follow-up is required to determine if curcumin can delay or prevent AD.
Alcohol
The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).54 Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).55 Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.55
The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.56 According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),57 moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).58
In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).59 In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.60 Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.54 However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.61 Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).61
Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.62 Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.13
Continue to: Coffee/tea
Coffee/tea
Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.66 Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.67 These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine,
An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.69 Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.70
Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.71 In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.72 More studies are needed to confirm its potential preventative role in AD.
Which lifestyle change is the most important?
Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.73
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities74:
- a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
- regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
- cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
- optimal management of cardiovascular risk factors.
Continue to: This multi-domain approach...
This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).
Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multidimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).75
On a practical basis, Desai et al13 have proposed a checklist (Table 213) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.
Bottom Line
Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.
Related Resources
- Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
- Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
- Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.
Drug Brand Name
Curcumin • Theracurmin
Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.1 An estimated one-third of AD cases can be attributed to modifiable risk factors.2 Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.
Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.3 Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”
Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.4
Physical exercise
Twenty-one percent of AD cases in the United States are attributable to physical inactivity.5 In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).6
The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.7 Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al8 categorized leisure-time activities into 3 types:
- light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
- moderate (bicycling, swimming, hiking, playing tennis)
- vigorous (aerobic dancing, jogging, playing handball).
These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).8
In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).9 Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).10
Continue to: From a pathophysiological standpoint...
From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.11 This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.12
Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.13 These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week14 (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).15
Mental activity
Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.5 Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.16 Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.17 Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.18 The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.19
In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.20 Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.21
Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.22 Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.23
Continue to: Physicians should encourage their patients...
Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).
Social activity
Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.24 Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).25 In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).26
A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.27 Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.28
Meditation/spiritual activity
Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.29 Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neurodegenerative processes of AD.30 In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).31 By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.
Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.32 Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control33 and functional connectivity in brain regions implicated in executive functioning,34 as well as by modulating inflammatory processes implicated in AD.35 Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.36
Continue to: Kirtan Kriya is a medication technique...
Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.37 However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).38
Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).39
Diet
In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.40 The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.41 A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.42 In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.43,44
Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.45 In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.46 Scarmeas et al8 found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neurocognitive improvement in patients with hypertension.47 Both the Mediterranean and DASH diets have been associated with better cognitive function48 and slower cognitive decline.49 Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.50
Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.51
Continue to: Curcumin, which is derived from...
Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.52 However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.53 A longer follow-up is required to determine if curcumin can delay or prevent AD.
Alcohol
The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).54 Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).55 Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.55
The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.56 According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),57 moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).58
In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).59 In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.60 Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.54 However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.61 Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).61
Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.62 Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.13
Continue to: Coffee/tea
Coffee/tea
Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.66 Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.67 These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine,
An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.69 Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.70
Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.71 In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.72 More studies are needed to confirm its potential preventative role in AD.
Which lifestyle change is the most important?
Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.73
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities74:
- a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
- regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
- cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
- optimal management of cardiovascular risk factors.
Continue to: This multi-domain approach...
This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).
Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multidimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).75
On a practical basis, Desai et al13 have proposed a checklist (Table 213) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.
Bottom Line
Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.
Related Resources
- Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
- Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
- Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.
Drug Brand Name
Curcumin • Theracurmin
1. Mehta D, Jackson R, Paul G, et al. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs. 2017;26(6):735-739.
2. Norton S, Matthews FE, Barnes DE, et al. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788-794.
3. Meng XF, Yu JT, Wang HF, et al. Midlife vascular risk factors and the risk of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;42(4):1295-1310.
4. Shekelle PG, Woolf SH, Eccles M, et al. Developing clinical guidelines. West J Med. 1999;170(6):348-351.
5. Barnes DE, Yaffe Y. The projected impact of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011;10(9):819-828.
6. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30(9):464-472.
7. Ahlskog JE, Geda YE, Graff-Radford NR, et al. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86(9):876-884.
8. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of Alzheimer Disease. JAMA. 2009;302(6):627-637.
9. Rovio S, Kåreholt I, Helkala EL, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol. 2005;4(11):705-711.
10. Smith PJ et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med. 2010;72(3):239-252.
11. Brown BM, Peiffer JJ, Taddei K, et al. Physical activity and amyloid-beta plasma and brain levels: results from the Australian imaging, biomarkers and lifestyle study of ageing. Mol Psychiatry. 2013;18(8):875-881.
12. Brown BM, Sohrabi HR, Taddei K, et al. Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer’s disease. Alzheimers Dement. 2017;13(11):1197-1206.
13. Desai AK, Grossberg GT, Chibnall JT. Healthy brain aging: a road map. Clin Geriatr Med. 2010;26(1):1-16.
14. Centers for Disease Control and Prevention. Physical activity: how much physical activity do older adults need?
15. Garber CE, Blissmer B, Deschenes MR, et al; American College of Sports Medicine. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc. 2011;43(7):1334-1359.
16. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113);2673-2734.
17. Valenzuela MJ, Sachdev P, Wen W, et al. Lifespan mental activity predicts diminished rate of hippocampal atrophy. PLoS One. 2008;3(7):e2598. doi.org/10.1371/journal.pone.0002598.
18. Wilson RS, Bennett DA, Bienias JL, et al. Cognitive activity and incident AD in a population-based sample of older persons. Neurology. 2002;59(12):1910-1914.
19. Wilson RS, Scherr PA, Schneider JA, et al. Relation of cognitive activity to risk of developing Alzheimer disease. Neurology. 2007;69(20):1911-1920.
20. Krell-Roesch J, Vemuri P, Pink A, et al. Association between mentally stimulating activities in late life and the outcome of incident mild cognitive impairment, with an analysis of the apoe ε4 genotype. JAMA Neurol. 2017;74(3):332-338.
21. Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med. 2003;348(25):2508-2516.
22. Klein RM, Christie J, Parkvall M. Does multilingualism affect the incidence of Alzheimer’s disease?: a worldwide analysis by country. SSM Popul Health. 2016;2:463-467.
23. Grundy JG, Anderson JAE, Bialystok E. Neural correlates of cognitive processing in monolinguals and bilinguals. Ann N Y Acad Sci. 2017;1396(1):183-201.
24. Wilson RS, Krueger KR, Arnold SE, et al. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry. 2007;64(2):234-240.
25. Amieva H, Stoykova R, Matharan F, et al. What aspects of social network are protective for dementia? Not the quantity but the quality of social interactions is protective up to 15 years later. Psychosom Med. 2010;72(9):905-911.
26. Kuiper JS, Oude Voshaar RC, Zuidema SU, et al. The relationship between social functioning and subjective memory complaints in older persons: a population-based longitudinal cohort study. Int J Geriatr Psychiatry. 2017;32(10):1059-1071.
27. Robert P, Onyike CU, Leentjens AF, et al. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. Eur Psychiatry. 2009;24(2):98-104.
28. Marioni RE, Proust-Lima C, Amieva H, et al. Social activity, cognitive decline and dementia risk: a 20-year prospective cohort study. BMC Public Health. 2015;15:1089.
29. Wilson RS, Schneider JA, Boyle PA, et al. Chronic distress and incidence of mild cognitive impairment. Neurology. 2007;68(24):2085-2092.
30. Cai Z, Yan LJ, Ratka A. Telomere shortening and Alzheimer’s disease. Neuromolecular Med. 2013;15(1):25-48.
31. Wilson RS, Arnold SE, Schneider JA, et al. Chronic psychological distress and risk of Alzheimer’s disease in old age. Neuroepidemiology. 2006;27(3):143-153.
32. Epel E, Daubenmier J, Moskowitz JT, et al. Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres. Ann N Y Acad Sci. 2009;1172:34-53.
33. Malinowski P, Moore AW, Mead Br, et al. Mindful aging: the effects of regular brief mindfulness practice on electrophysiological markers of cognitive and affective processing in older adults. Mindfulness (N Y). 2017;8(1):78-94.
34. Taren AA, Gianaros PJ, Greco CM, et al. Mindfulness meditation training and executive control network resting state functional connectivity: a randomized controlled trial. Psychosom Med. 2017;79(6):674-683.
35. Fountain-Zaragoza S, Prakash RS. Mindfulness training for healthy aging: impact on attention, well-being, and inflammation. Front in Aging Neurosci. 2017;9:11.
36. Eyre HA, Siddarth P, Acevedo B, et al. A randomized controlled trial of Kundalini yoga in mild cognitive impairment. Int Psychogeriatr. 2017;29(4):557-567.
37. Khalsa DS. Stress, meditation, and Alzheimer’s disease prevention: where the evidence stands. J Alzheimers Dis. 2015;48(1):1-12.
38. Berk L, van Boxtel M, van Os J. Can mindfulness-based interventions influence cognitive functioning in older adults? A review and considerations for future research. Aging Ment Health. 2017;21(11):1113-1120.
39. Hosseini S, Chaurasia A, Oremus M. The effect of religion and spirituality on cognitive function: a systematic review. Gerontologist. 2017. doi: 10.1093/geront/gnx024.
40. Luchsinger JA, Tang MX, Shea S, et al. Caloric intake and the risk of Alzheimer disease. Arch Neurol. 2002;59(8):1258-1263.
41. Grant WB. Trends in diet and Alzheimer’s disease during the nutrition transition in Japan and developing countries. J Alzheimers Dis. 2014;38(3):611-620.
42. Kanoski SE, Davidson TL. Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol Behav. 2011;103(1):59-68.
43. Hu N, Yu JT, Tan L, et al. Nutrition and the risk of Alzheimer’s disease. Biomed Res Int. 2013;2013:524820. doi: 10.1155/2013/524820.
44. Taylor MK, Sullivan DK, Swerdlow RH, et al. A high-glycemic diet is associated with cerebral amyloid burden in cognitively normal older adults. Am J Clin Nutr. 2017;106(6):1463-1470.
45. van de Rest O, Berendsen AM, Haveman-Nies A, et al. Dietary patterns, cognitive decline, and dementia: a systematic review. Adv Nutr. 2015;6(2):154-168.
46. Petersson SD, Philippou E. Mediterranean diet, cognitive function, and dementia: a systematic review of the evidence. Adv Nutr. 2016;7(5):889-904.
47. Smith PJ, Blumenthal JA, Babyak MA, et al. Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure. Hypertension. 2010;55(6):1331-1338.
48. Wengreen H, Munger RG, Cutler A, et al. Prospective study of dietary approaches to stop hypertension- and Mediterranean-style dietary patterns and age-related cognitive change: the Cache County study on memory, health and aging. Am J Clin Nutr. 2013;98(5):1263-1271.
49. Tangney CC, Li H, Wang Y, et al. Relation of DASH- and Mediterranean-like dietary patterns to cognitive decline in older persons. Neurology. 2014;83(16):1410-1416.
50. Morris MC, Tangney CC, Wang Y, et al. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement. 2015;11(9):1007-1014.
51. Desai AK, Rush J, Naveen L, et al. Nutrition and nutritional supplements to promote brain health. In: Hartman-Stein PE, Rue AL, eds. Enhancing cognitive fitness in adults: a guide to the use and development of community-based programs. New York, NY: Springer; 2011:249-269.
52. Goozee KG, Shah TM, Sohrabi HR, et al. Examining the potential clinical value of curcumin in the prevention and diagnosis of Alzheimer’s disease. Br J Nutr. 2016;115(3):449-465.
53. Small GW, Siddarth P, Li Z, et al. Memory and brain amyloid and tau effects of a bioavailable form of curcumin in non-demented adults: a double-blind, placebo-controlled 18-month trial. Am J Geriatr Psychiatry. 2018;26(3):266-277.
54. Kim JW, Lee DY, Lee BC, et al. Alcohol and cognition in the elderly: a review. Psychiatry Investig. 2012;9(1):8-16.
55. Virtaa JJ, Järvenpää T, Heikkilä K, et al. Midlife alcohol consumption and later risk of cognitive impairment: a twin follow-up study. J Alzheimers Dis. 2010;22(3):939-948.
56. Kerr WC, Stockwell T. Understanding standard drinks and drinking guidelines. Drug and Alcohol Rev. 2012;31(2):200-205.
57. National Institute on Alcohol Abuse and Alcoholism. Drinking levels defined. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking. Accessed December 9, 2017.
58. National Institute on Alcohol Abuse and Alcoholism. What is a standard drink? https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/what-standard-drink. Accessed November 9, 2017.
59. Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian study of health and aging. Am J Epidemiol. 2002;156(5):445-453.
60. Orgogozo JM, Dartigues JF, Lafont S, et al. Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol (Paris). 1997;153(3):185-192.
61. Topiwala A, Allan CL, Valkanova V, et al. Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study. BMJ. 2017;357.
62. Venkataraman A, Kalk N, Sewell G, et al. Alcohol and Alzheimer’s disease-does alcohol dependence contribute to beta-amyloid deposition, neuroinflammation and neurodegeneration in Alzheimer’s Disease? Alcohol Alcohol. 2017;52(2):151-158.
63. Ma QP, Huang C, Cui QY, et al. Meta-analysis of the association between tea intake and the risk of cognitive disorders. PLoS One. 2016;11(11):e0165861. doi: 10.1371/journal.pone.0165861.
64. Santos C, Costa J, Santos J, et al. Caffeine intake and dementia: systematic review and meta-analysis. J Alzheimers Dis. 2010;20(Suppl 1):S187-204.
65. Panza F, Solfrizzi V, Barulli MR, et al. Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review. J Nutr Health Aging. 2015;19(3):313-328.
66. Wierzejska R. Can coffee consumption lower the risk of Alzheimer’s disease and Parkinson’s disease? A literature review. Arch Med Sci. 2017;13(3):507-514.
67. Arendash GW, Cao C. Caffeine and coffee as therapeutics against Alzheimer’s disease. J Alzheimers Dis. 2010;20 (Suppl 1):S117-S126.
68. Eskelinen MH, Ngandu T, Tuomilehto J, et al. Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J Alzheimers Dis. 2009;16(1):85-91.
69. Solfrizzi V, Panza F, Imbimbo BP, et al. Coffee consumption habits and the risk of mild cognitive impairment: the Italian longitudinal study on aging. J Alzheimers Dis. 2015;47(4):889-899.
70. Vittoria Mattioli. Beverages of daily life: impact of caffeine on atrial fibrillation. J Atr Fibrillation. 2014;7(2):1133.
71. Chacko SM, Thambi PT, Kuttan R, et al. Beneficial effects of green tea: a literature review. Chin Med. 2010;5:13.
72. Noguchi-Shinohara M, Yuki S, Dohmoto C, et al. Consumption of green tea, but not black tea or coffee, is associated with reduced risk of cognitive decline. PLoS One. 2014;9(5):e96013. doi: 10.1371/journal.pone.0096013.
73. Schneider N, Yvon C. A review of multidomain interventions to support healthy cognitive ageing. J Nutr Health Aging. 2013;17(3):252-257.
74. Ngandu T, Lehitsalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255-2263.
75. U.S. National Library of Medicing. ClinicalTrials.gov. U.S. study to protect brain health through lifestyle intervention to reduce risk (POINTER). https://clinicaltrials.gov/ct2/show/NCT03688126?term=pointer&cond=Alzheimer+Disease&rank=1. Published September 28, 2018. Accessed November 3, 2018.
1. Mehta D, Jackson R, Paul G, et al. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs. 2017;26(6):735-739.
2. Norton S, Matthews FE, Barnes DE, et al. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788-794.
3. Meng XF, Yu JT, Wang HF, et al. Midlife vascular risk factors and the risk of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;42(4):1295-1310.
4. Shekelle PG, Woolf SH, Eccles M, et al. Developing clinical guidelines. West J Med. 1999;170(6):348-351.
5. Barnes DE, Yaffe Y. The projected impact of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011;10(9):819-828.
6. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30(9):464-472.
7. Ahlskog JE, Geda YE, Graff-Radford NR, et al. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86(9):876-884.
8. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of Alzheimer Disease. JAMA. 2009;302(6):627-637.
9. Rovio S, Kåreholt I, Helkala EL, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol. 2005;4(11):705-711.
10. Smith PJ et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med. 2010;72(3):239-252.
11. Brown BM, Peiffer JJ, Taddei K, et al. Physical activity and amyloid-beta plasma and brain levels: results from the Australian imaging, biomarkers and lifestyle study of ageing. Mol Psychiatry. 2013;18(8):875-881.
12. Brown BM, Sohrabi HR, Taddei K, et al. Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer’s disease. Alzheimers Dement. 2017;13(11):1197-1206.
13. Desai AK, Grossberg GT, Chibnall JT. Healthy brain aging: a road map. Clin Geriatr Med. 2010;26(1):1-16.
14. Centers for Disease Control and Prevention. Physical activity: how much physical activity do older adults need?
15. Garber CE, Blissmer B, Deschenes MR, et al; American College of Sports Medicine. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc. 2011;43(7):1334-1359.
16. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113);2673-2734.
17. Valenzuela MJ, Sachdev P, Wen W, et al. Lifespan mental activity predicts diminished rate of hippocampal atrophy. PLoS One. 2008;3(7):e2598. doi.org/10.1371/journal.pone.0002598.
18. Wilson RS, Bennett DA, Bienias JL, et al. Cognitive activity and incident AD in a population-based sample of older persons. Neurology. 2002;59(12):1910-1914.
19. Wilson RS, Scherr PA, Schneider JA, et al. Relation of cognitive activity to risk of developing Alzheimer disease. Neurology. 2007;69(20):1911-1920.
20. Krell-Roesch J, Vemuri P, Pink A, et al. Association between mentally stimulating activities in late life and the outcome of incident mild cognitive impairment, with an analysis of the apoe ε4 genotype. JAMA Neurol. 2017;74(3):332-338.
21. Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med. 2003;348(25):2508-2516.
22. Klein RM, Christie J, Parkvall M. Does multilingualism affect the incidence of Alzheimer’s disease?: a worldwide analysis by country. SSM Popul Health. 2016;2:463-467.
23. Grundy JG, Anderson JAE, Bialystok E. Neural correlates of cognitive processing in monolinguals and bilinguals. Ann N Y Acad Sci. 2017;1396(1):183-201.
24. Wilson RS, Krueger KR, Arnold SE, et al. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry. 2007;64(2):234-240.
25. Amieva H, Stoykova R, Matharan F, et al. What aspects of social network are protective for dementia? Not the quantity but the quality of social interactions is protective up to 15 years later. Psychosom Med. 2010;72(9):905-911.
26. Kuiper JS, Oude Voshaar RC, Zuidema SU, et al. The relationship between social functioning and subjective memory complaints in older persons: a population-based longitudinal cohort study. Int J Geriatr Psychiatry. 2017;32(10):1059-1071.
27. Robert P, Onyike CU, Leentjens AF, et al. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. Eur Psychiatry. 2009;24(2):98-104.
28. Marioni RE, Proust-Lima C, Amieva H, et al. Social activity, cognitive decline and dementia risk: a 20-year prospective cohort study. BMC Public Health. 2015;15:1089.
29. Wilson RS, Schneider JA, Boyle PA, et al. Chronic distress and incidence of mild cognitive impairment. Neurology. 2007;68(24):2085-2092.
30. Cai Z, Yan LJ, Ratka A. Telomere shortening and Alzheimer’s disease. Neuromolecular Med. 2013;15(1):25-48.
31. Wilson RS, Arnold SE, Schneider JA, et al. Chronic psychological distress and risk of Alzheimer’s disease in old age. Neuroepidemiology. 2006;27(3):143-153.
32. Epel E, Daubenmier J, Moskowitz JT, et al. Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres. Ann N Y Acad Sci. 2009;1172:34-53.
33. Malinowski P, Moore AW, Mead Br, et al. Mindful aging: the effects of regular brief mindfulness practice on electrophysiological markers of cognitive and affective processing in older adults. Mindfulness (N Y). 2017;8(1):78-94.
34. Taren AA, Gianaros PJ, Greco CM, et al. Mindfulness meditation training and executive control network resting state functional connectivity: a randomized controlled trial. Psychosom Med. 2017;79(6):674-683.
35. Fountain-Zaragoza S, Prakash RS. Mindfulness training for healthy aging: impact on attention, well-being, and inflammation. Front in Aging Neurosci. 2017;9:11.
36. Eyre HA, Siddarth P, Acevedo B, et al. A randomized controlled trial of Kundalini yoga in mild cognitive impairment. Int Psychogeriatr. 2017;29(4):557-567.
37. Khalsa DS. Stress, meditation, and Alzheimer’s disease prevention: where the evidence stands. J Alzheimers Dis. 2015;48(1):1-12.
38. Berk L, van Boxtel M, van Os J. Can mindfulness-based interventions influence cognitive functioning in older adults? A review and considerations for future research. Aging Ment Health. 2017;21(11):1113-1120.
39. Hosseini S, Chaurasia A, Oremus M. The effect of religion and spirituality on cognitive function: a systematic review. Gerontologist. 2017. doi: 10.1093/geront/gnx024.
40. Luchsinger JA, Tang MX, Shea S, et al. Caloric intake and the risk of Alzheimer disease. Arch Neurol. 2002;59(8):1258-1263.
41. Grant WB. Trends in diet and Alzheimer’s disease during the nutrition transition in Japan and developing countries. J Alzheimers Dis. 2014;38(3):611-620.
42. Kanoski SE, Davidson TL. Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol Behav. 2011;103(1):59-68.
43. Hu N, Yu JT, Tan L, et al. Nutrition and the risk of Alzheimer’s disease. Biomed Res Int. 2013;2013:524820. doi: 10.1155/2013/524820.
44. Taylor MK, Sullivan DK, Swerdlow RH, et al. A high-glycemic diet is associated with cerebral amyloid burden in cognitively normal older adults. Am J Clin Nutr. 2017;106(6):1463-1470.
45. van de Rest O, Berendsen AM, Haveman-Nies A, et al. Dietary patterns, cognitive decline, and dementia: a systematic review. Adv Nutr. 2015;6(2):154-168.
46. Petersson SD, Philippou E. Mediterranean diet, cognitive function, and dementia: a systematic review of the evidence. Adv Nutr. 2016;7(5):889-904.
47. Smith PJ, Blumenthal JA, Babyak MA, et al. Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure. Hypertension. 2010;55(6):1331-1338.
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49. Tangney CC, Li H, Wang Y, et al. Relation of DASH- and Mediterranean-like dietary patterns to cognitive decline in older persons. Neurology. 2014;83(16):1410-1416.
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