INSIGHTS Primary Prevention of Dementia Evidence for modifiable lifestyle factors for dementia prevention is growing. By Chen Zhao, MD, MS; Jonathan G. Hakun, PhD; K. Sathian, MBBS, PhD; and Nikolaos Scarmeas, MD, MS, PhD

An estimated 44 to 47 million Overweight or people are living with demen- Obesity is associated with myriad neurologic consequences, tia worldwide.1 Dementia is a including increased stroke risk,9 poor cognition and dementia, significant cause of morbidity autonomic dysfunction, and polyneuropathy.10 Consistent and mortality among the aging with recommendations from the American Heart Association population,1 with high econom- and the American College of Cardiology, the US Preventive ic costs and significant burden Services Task Force (USPSTF) recommends all obese adults be on caregivers.2 No disease-mod- offered or referred to intensive multicomponent behavioral ifying treatment for dementia interventions. Behavioral counseling to promote a healthy yet exists. Although primary diet and physical activity is recommend for adults who are prevention remains an elusive overweight or obese and also have cardiovascular risk fac- goal, modifiable risk factors may tors.10 Overweight and obese participants in 1 study had nearly account for up to 35% of the dementia burden.3 twice the odds of reporting a 5% weight loss in the past year if The study of lifestyle factors and dementia risk is inher- their physicians merely informed them they were overweight. ently challenging because of residual confounding in obser- Furthermore, these patients had more than twice the odds of vational studies and attrition in clinical trials of lifestyle reporting more than 10% weight loss if their physicians had interventions. Although there is insufficient evidence to actively discussed their weight status.11 Another study found establish public health guidelines for primary prevention that individuals diagnosed as obese or overweight by a health- of dementia,4 the extant epidemiologic evidence justifies care provider were more likely to pursue lifestyle changes to counseling patients to make lifestyle changes both for global control their weight.12 Considering the significant impact of health benefits and potential dementia risk modification. obesity on neurologic outcomes, it is reasonable for the neu- In this selective review we aim to provide an update of rologist to discuss weight status with patients. current knowledge on primary prevention of dementia with a practical focus on counseling patients on making relevant Physical Activity lifestyle modifications. Specifically, we focus on clinical man- Physical activity promotes recovery after ischemic insult, agement of comorbidities (vascular risk/protective factors), and neuronal survival after neurotoxic injury in animal mod- counseling on diet, cognitive activities, and sleep. We also els. Insulin-like growth factor is a potential mediator of these offer suggestions for fielding common questions on the rela- neuroprotective effects.13 Physical activity also promotes brain tionship between lifestyle factors and dementia risk. maintenance, builds cognitive reserve, and may even reduce accumulation of brain pathology.14,15 The World Health Vascular Factors Organization recommends 150 minutes of moderate-intensity By some estimates 90% of stroke is preventable.5 Stroke is or 75 minutes of vigorous-intensity aerobic activity per week an independent risk factor, approximately doubling dementia for adults ages 18 to 64 and suggests additional benefits from risk, and mixed pathologies are common.6,7 Stroke and demen- doubling the weekly duration of activity. Muscle strengthen- tia likely share some modifiable risk and protective factors.8 ing activities on 2 or more days a week are recommended.16 Considering this evidence, the World Stroke Organization’s Stated goals for these recommendations are to improve call for the joint prevention of stroke and dementia has been cardiorespiratory and muscular fitness and bone health and endorsed by 23 international, regional, and national organiza- reduce the risk of noncommunicable diseases and depression. tions, including the American Academy of Neurology. These recommendations are essentially identical to the 2018

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Physical Activity Guidelines for Americans (PAG),17 although ment for may prevent, delay, or slow clinical the WHO recommends aerobic activity periods last at least Alzheimer-type dementia.4 The USPSTF is updating 2015 10 minutes, whereas US PAG suggests small increases in physi- recommendations to screen for high in adults cal activity (eg, parking further away) may still be of benefit. age 18 years or more.10 Lifestyle modification is the first line What amount of activity is needed to benefit the brain, of antihypertensive treatment,25 and the Dietary Approaches however, remains unclear. A recent randomized clinical trial to Stop Hypertension (DASH) diet is effective in treating found that 6 months of aerobic (40 to 55 min/ses- hypertension with an effect size comparable to drug mono- sion in 4 sessions/week) improved executive function among therapy.26 Hypertension can also be secondary to comorbid adults age 20 to 67, with a stronger effect observed in adults conditions (eg, obstructive sleep apnea) that may be revers- more than age 38.18 These results are consistent with a previ- ible causes of cognitive impairment and should not be missed ous trial showing a 1-year aerobic exercise intervention selec- during the neurologic assessment. tively increased anterior hippocampal volume by 2%, offset- Similar considerations apply for screening and manage- ting the annual 1% to 2% volume loss associated with aging.19 ment of other vascular risk factors, including hyperlipidemia A systematic review of 19 randomized clinical trials (most last- and . In particular, there is evidence that impaired ing <1 year) concluded there is encouraging but inconclusive insulin signaling occurs in the early stages of cognitive impair- evidence that physical activity may delay or slow age-related ment, leading some to propose that Alzheimer disease may cognitive decline and insufficient evidence of whether physical represent “type 3 diabetes.”27 There is currently insufficient activity prevents or delays clinical Alzheimer-type dementia.4 evidence (because of too few randomized controlled trials) to determine the effectiveness of lipid-lowering treatment Smoking (statins) and diabetes treatment for preventing age-related Smoking doubles stroke risk in a dose-dependent relation- cognitive decline or clinical Alzheimer type dementia; both ship in which every 5 additional cigarettes per day increases are recognized priorities for future research.4 Clinical guide- stroke risk 12%.20 Studies on the association between smoking lines and recommendations for management are provided for and dementia, however, have found varying results. Some have each vascular factor in the supplemental interactive Appendix employed short follow-up times, and other studies that have in the online version of this article. Our interpretation of how examined smoking in midlife were conducted in homogenous to use this information is summarized in Box 1. populations. A large study in a multiethnic cohort with a mean follow-up period of 23 years found an association between Diet heavy smoking during midlife and increased long-term demen- There are multiple ways to examine the relationship tia risk.21 A meta-analysis found current smokers have 30% between diet and cognitive outcomes. Studies have focused increased dementia risk, although survivor bias and compet- on individual micro- and macronutrients, food groups, and ing risks likely make this an underestimation of effect size.22 dietary patterns. Most studies of specific nutrients or diet are Of note, epidemiologic studies have consistently found an observational (Tables 1-3), although some notable clinical association between smoking and decreased risk of Parkinson trials of , antioxidants, and fatty acids have largely disease.23 Further research is needed to elucidate the biological observed no significant effect with a few showing protective mechanisms underlying this relationship. The USPSTF recom- effects.28 Studies of food groups have been almost entirely mends clinicians ask all adults about tobacco use.10 Providing observational, with the notable exception of some clinical trials minimal intervention by simply asking about smoking and on olive oil and seeds intake.28 Overall, the evidence is stron- recommending cessation can be valuable.24 Smokefree.gov is a useful resource that provides targeted smoking cessation Box 1. Hypertension—Interpreting resources to address the needs of specific populations, includ- ing women (notably pregnant women), people in their teens the Evidence or over age 60, veterans, and Spanish-speakers. • Counseling on vascular risk factors is part of primary and secondary stroke prevention and analogously a compo- Hypertension nent of dementia prevention and care. In the SPRINT trial,a intensive vs regular blood pressure • When time does not permit in-depth counseling, simply control (systolic blood pressure [SBP] <120 mm Hg vs acknowledging the patient’s current weight status and 140 mm Hg) did not significantly reduce probable demen- asking about smoking habits may be beneficial. tiarisk but did reduce the risk for mild cognitive impairment • Although it has not been studied, it may be that specialist (MCI). Positive evidence from prospective cohort studies and counseling could have a synergistic effect when combined mixed results from randomized clinical trials provide encour- with primary-care counseling. aging but inconclusive evidence that blood pressure manage-

a Systolic Blood Pressure Intervention Trial (NCT01206062) 62 PRACTICAL NEUROLOGY OCTOBER 2020 DEMENTIA INSIGHTS

TABLE 1. DIET AND COGNITION: SUMMARY OF TABLE 2. DIET AND COGNITION: SUMMARY OF RESEARCH FINDINGS FOR SPECIFIC NUTRIENTS RESEARCH FINDINGS FOR SPECIFIC FOODS/DRINKS Dietary component Observational studies Clinical trials Dietary component Observational studies Clinical trials Minerals and Vitamins Alcohol (moderate vs none) llllllll B complex lllll Alcohol (moderate vs high) lll lllll Moderate wine intake llllll lllllll Moderate beer intake llll lllllll l Moderate other spirits lllll B complex lllll Coffee lllllllll llllllllll l Tea llllll Antioxidant multivitamin lll Caffeine llll Anthocyanidins l Fish and seafood lllllll Vitamin C llllll Meat l Carotenoids lllllll Dairy lll Copper l Legumes ll Vitamin E lllllll l Vegetables lllll Flavoids/polyphenols llllllll Fruit llll Selenium l l Fruits and vegetables lll Dietary Lipids/Lipidemic Profile Juices ll Total dietary llll Olive oil Saturated fatty acids (FA) llllllllll Seeds ll Total polyunsaturated FA lllll lprotective effect; lno significant effect; ldetrimental effect. Monounsaturated FA lllllll Adapted from Scarmeas N, Anastasiou CA, Yannakoulia M. n-3 polyunsaturated FA llllllll lllllll Nutrition and prevention of cognitive impairment. Lancet Neurol. 2018;17(11):1006-1015. Trans FA lll llll ries, and not specifying high fish, fruit, or dairy intake. The US lprotective effect; lno significant effect; ldetrimental effect. Dietary Guidelines (2015-2020) recommend the MeDi, DASH, Adapted from Scarmeas N, Anastasiou CA, Yannakoulia M. and a vegetarian diet as examples of healthy eating patterns.30 Nutrition and prevention of cognitive impairment. Lancet Based on available data, it is reasonable to counsel patients Neurol. 2018;17(11):1006-1015. to increase intake of particular food groups, including vegeta- bles, fruits, fish, olive oil, and nuts. Depending on patient pref- ger for an association between dietary patterns and cognitive erence, we recommend providing examples of healthy dietary outcomes, than for individual nutrients or food groups and patterns (eg, MeDi) that are described in the US Dietary cognitive outcomes.28,29 Guidelines (2015-2020). It should be noted that lifestyle behav- The Mediterranean diet (MeDi) is the best studied dietary iors may confound the study of dietary patterns. For example, pattern, consisting of high intake of vegetables, legumes, studies of MeDi have not typically accounted for other aspects fruits, and cereals; moderate intake of fish; low intake of meat of the Mediterranean lifestyle such as sharing meals, length of and poultry, and low-to-moderate intake of dairy products. meals, and siestas.31 With careful attention to study design, it Moderate alcohol intake, generally during meals, is part of may be possible to tease out the effects of diet, independent of MeDi, as is high intake of unsaturated fatty acids (eg, olive oil) these confounding factors. with low intake of saturated fatty acids. DASH is another well- Caloric restriction extends lifespan in animal models and studied dietary pattern that is high in vegetables and fruits and holds promise as a potential intervention in humans. In the low in fat. DASH has been shown effective in decreasing blood first human clinical trials of calorie restriction, 2 years of mod- pressure, both in hypertensive and prehypertensive individuals. erate calorie restriction significantly reduced cardiometabolic The Mediterranean-DASH Intervention for Neurodegenerative risk factors in young nonobese adults. These findings are Delay (MIND) diet is a hybrid of the MeDi and DASH diet consistent with observations collected from members of the focused on plant-based foods and limited intake of saturated Calorie Restriction Society, who have been voluntarily restrict- fat, specifying consumption of green leafy vegetables and ber- ing caloric intake to ~1800 kcal/day for an average of 15 years,

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TABLE 3. DIET AND COGNITION: SUMMARY OF no evidence that cognitive training reduces the risk of clinical RESEARCH FINDINGS FOR SPECIFIC DIET PATTERNS Alzheimer-type dementia in individuals with normal cogni- Dietary pattern Observational Clinical tion or MCI.4 These conclusions were drawn largely from a studies trials single large randomized trial (n=2,802) of cognitive training 34 Alternative healthy eating index l in community-dwelling adults more than age 65. In this trial, cognitive training had long-term (10‑year) effects on self- Dietary approaches to stop hyper- lll tension (DASH) reported maintenance of instrumental activities of daily living (ADLs), but training effects on specific cognitive abilities dissi- Dietary quality score (CARDIA study) l pated slowly over time. Consensus recommendations from the l Healthy diet indicator (WHO) Global Council on Brain Health (GCBH)35 suggest cognitively Healthy eating index l stimulating activities over the life course (including formal or Low carbohydrate, high protein diet l informal educational activities) provide benefits to adult brain Mediterranean diet (MeDi) lllllllll lll health. There is evidence that participation in leisure activities llll is associated with reduced dementia risk independent of edu- MIND (parts of DASH and MeDi) llll cation level.36 If patients enjoy particular mentally stimulating Multidomain interventions lllll activities such as Sudoku, particularly if these activities involve social interaction, they should be encouraged to continue Nordic diet score ll those activities. Population-specific prudent diets lll lprotective; lno significant effect. Sleep Observational studies show consistent associations between while maintaining optimal nutrition.32 Further studies are sleep-disordered breathing and cognition.37 Compared with needed before caloric restriction can be safely recommended other modifiable lifestyle risk factors, however, modifying sleep to patients as a viable lifestyle modification (Box 2). patterns and disorders is challenging. Although treatment of sleep apnea is relatively straightforward, adherence to treat- Cognitive Activities ment can be challenging. Treatment for other sleep disorders Observational studies suggest that cognitive activities may (eg, insomnia, REM sleep behavior disorder, circadian rhythm enhance cognitive reserve,14 which compensates for both dysfunction) varies considerably. Exercise is associated with age-related brain changes and pathologic changes of demen- better sleep in epidemiologic studies, although reverse causa- tia. Although education in early life builds cognitive reserve, tion is possible.38 To our knowledge, there are no randomized individuals with higher educational and occupational attain- controlled trials on sleep interventions for the primary preven- ment may exhibit more rapid cognitive decline.33 This could tion of dementia yet, making it unclear whether poor sleep be because highly educated individuals compensate better for precedes dementia as a potential modifiable risk factor or is a mild symptoms and do not present until more severe symp- consequence of dementia. toms present along with a higher level of neuropathology. Biologically, several mechanisms related to sleep dysfunc- There is encouraging but inconclusive evidence that cognitive tion could potentially lead to developing dementia. Chronic training may delay or slow age-related cognitive decline but intermittent hypoxemia could lead to microvascular changes and subsequent cognitive impairment.37 The sleep-wake cycle Box 2. Diet: Interpreting the Evidence regulates glymphatic clearance, and may decrease amyloid clearance.39-41 • It is important to remember the challenges of studying It has been suggested that screening for sleep-disordered diet when interpreting the results of observational studies breathing should be included in the clinical evaluation of and clinical trials on diet and cognition. cognitive impairment in adults.42 The GCBH 2017 consen- • It is reasonable to counsel patients to increase intake of sus lists chronic inadequate sleep as a risk for more severe vegetables, fruits, nuts, and fish, which have been found dementia. This consensus also notes that although sleep protective for cognition in observational studies. quality changes with aging, persistent daytime sleepiness is not part of normal aging, and behavior change to improve • Considering the stronger evidence for dietary patterns 43 compared with micronutrients, we recommend instruct- sleep is possible at all ages (Box 3). ing patients to follow a healthy dietary pattern (eg, MeDi, DASH, MIND) over focusing on supplementing the diet Conclusion—Fielding Questions from Patients with particular micronutrients. When discussing lifestyle factors and risk for dementia with patients, we suggest an evidence-based approach tai-

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29. Zhao C, Noble JM, Marder K, Hartman JS, Gu Y, Scarmeas N. Dietary patterns, physical activity, sleep, and risk for dementia and cognitive decline. Curr Nutr Rep. 2018;7(4):335-345. 30. 2015-2020 Dietary Guidelines for Americans. U.S. Department of Health and Human Services and U.S. Department of Agricul- Box 3. Sleep: Interpreting the Evidence ture. Published December 2015. Accessed July 18, 2020. http://health.gov/dietaryguidelines/2015/guidelines 31. Yannakoulia M, Kontogianni M, Scarmeas N. Cognitive health and Mediterranean diet: just diet or lifestyle pattern? Ageing Res • Remaining cognitively active with mentally stimulating Rev. 2015;20:74-78. activities may contribute to cognitive reserve. 32. Kraus WE, Bhapkar M, Huffman KM, et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(9):673-683. • Observational evidence links poor sleep and dementia risk; 33. Stern Y, Albert S, Tang MX, Tsai WY. Rate of memory decline in AD is related to education and occupation: cognitive reserve? Neurology. 1999;53(9):1942-1947. • We recommend screening patients with cognitive impair- 34. Rebok GW, Ball K, Guey LT, et al. Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive ment for sleep dysfunction. training trial on cognition and everyday functioning in older adults. J Am Geriatr Soc. 2014;62(1):16-24. 35. Global Council on Brain Health. Engage Your Brain: GCBH Recommendations on Cognitively Stimulating Activities. Global Council on Brain Health; 2017. lored to the individual patient’s needs without rigid adher- 36. Scarmeas N, Levy G, Tang MX, Manly J, Stern Y. Influence of leisure activity on the incidence of Alzheimer’s disease. Neurology. ence to consensus recommendations. The study of lifestyle 2001;57(12):2236-2242. 37. Zimmerman ME, Aloia MS. Sleep-disordered breathing and cognition in older adults. Curr Neurol Neurosci Rep. 2012;12(5):537-546. factors and dementia risk is fraught with methodologic 38. Youngstedt SD, Kline CE. Epidemiology of exercise and sleep. Sleep Biol Rhythms. 2006;4(3):215-221. difficulties. It is important to keep these limitations in mind 39. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377. 40. Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JAHR. Effect of 1 night of total sleep deprivation on cerebrospinal when interpreting the evidence. For a list of common ques- fluid b-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 2014;71(8):971-977. tions from patients and our suggested possible responses, 41. Sprecher KE, Koscik RL, Carlsson CM, et al. Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults. Neurology. 2017;89(5):445-453. see Table e1 in the online version of this article. n 42. Auerbach S, Yaffe K. The link between sleep-disordered breathing and cognition in the elderly: new opportunities? Neurology. 2017;88(5):424-425. 1. GBD 2016 Dementia Collaborators. Global, regional, and national burden of Alzheimer’s disease and other , 1990- 43. Global Council on Brain Health. The Brain-Sleep Connection: GCBH Recommendations on Sleep and Brain Health. Global Council 2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):88-106. on Brain Health; 2017. 2. Roepke SK, Allison M, Von Känel R, et al. Relationship between chronic stress and carotid intima-media thickness (IMT) in elderly Alzheimer’s disease caregivers. Stress Amst Neth. 2012;15(2):121-129. 3. Orgeta V, Mukadam N, Sommerlad A, Livingston G. The Lancet Commission on Dementia Prevention, Intervention, and Care: a call for action. Ir J Psychol Med. 2019;36(2):85-88. Chen Zhao, MD, MS 4. National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Health Sciences Department of Neurology Policy, Committee on Preventing Dementia and Cognitive Impairment. Preventing Cognitive Decline and Dementia: A Way Forward. (Downey A, Stroud C, Landis S, Leshner AI, eds.). National Academies Press (US); 2017. Accessed May 14, 2018. Penn State Health Milton S. Hershey Medical Center http://www.ncbi.nlm.nih.gov/books/NBK436397/ Department of Public Health Sciences 5. Boyle PA, Yu L, Leurgans SE, et al. Attributable risk of Alzheimer’s dementia attributed to age-related neuropathologies. Ann Neurol. 2019;85(1):114-124. Pennsylvania State University College of Medicine 6. Kuzma E, Lourida I, Moore SF, Levine DA, Ukoumunne OC, Llewellyn DJ. Stroke and dementia risk: A systematic review and Hershey, PA meta-analysis. Alzheimers Dement . 2018;14(11):1416-1426. 7. Hachinski V, Einhäupl K, Ganten D, et al. Preventing dementia by preventing stroke: The Berlin Manifesto. Alzheimers Dement J Alzheimers Assoc. 2019;15(7):961-984. K. Sathian, MBBS, PhD 8. Strazzullo P, D’Elia L, Cairella G, Garbagnati F, Cappuccio FP, Scalfi L. Excess body weight and incidence of stroke: meta- analysis of prospective studies with 2 million participants. Stroke. 2010;41(5):e418-426. Department of Neurology 9. O’Brien PD, Hinder LM, Callaghan BC, Feldman EL. Neurological consequences of obesity. Lancet Neurol. 2017;16(6):465-477. Penn State Health Milton S. Hershey Medical Center 10. U.S. Preventive Services Task Force: A and B Recommendations. U.S. Preventive Services Task Force. Accessed August 14, 2020. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/uspstf-and-b-recommendations Department of Neural & Behavioral Sciences 11. Pool AC, Kraschnewski JL, Cover LA, et al. The impact of physician weight discussion on weight loss in US adults. Obes Res Pennsylvania State University College of Medicine Clin Pract. 2014;8(2):e131-139. 12. Yaemsiri S, Slining MM, Agarwal SK. Perceived weight status, overweight diagnosis, and weight control among US adults: Department of Psychology, Pennsylvania State University the NHANES 2003-2008 Study. Int J Obes. 2005. 2011;35(8):1063-1070. Hershey, PA 13. Zheng H-Q, Zhang L-Y, Luo J, et al. Physical exercise promotes recovery of neurological function after ischemic stroke in rats. Int J Mol Sci. 2014;15(6):10974-10988. 14. Stern Y, Arenaza-Urquijo EM, Bartrés-Faz D, et al. Whitepaper: Defining and investigating cognitive reserve, brain reserve, Jonathan G. Hakun, PhD and brain maintenance. Alzheimers Dement. 2018;S1552-5260(18):33491-33495. 15. Mortimer JA, Stern Y. Physical exercise and activity may be important in reducing dementia risk at any age. Neurology. Department of Neurology 2019;92(8):362-363. Pennsylvania State University College of Medicine 16. Organisation mondiale de la santé. Global Recommendations on Physical Activity for Health. WHO; 2010. 17. Piercy KL, Troiano RP, Ballard RM, et al. The Physical Activity Guidelines for Americans. JAMA. 2018;320(19):2020. Department of Psychology, Pennsylvania State University 18. Stern Y, MacKay-Brandt A, Lee S, McKinley P, McIntyre K, Razlighi Q, Agarunov E, Bartels M, Sloan RP. Effect of aerobic Hershey, PA exercise on cognition in younger adults: a randomized clinical trial. Neurology. 2019 Feb 26;92(9):e905-e916. 19. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108(7):3017-3022. Nikolaos Scarmeas, MD, MS, PhD 20. Pan B, Jin X, Jun L, Qiu S, Zheng Q, Pan M. The relationship between smoking and stroke: a meta-analysis. Medicine (Baltimore). 2019;98(12):e14872. 1st Department of Neurology, Aiginitio Hospital 21. Rusanen M, Kivipelto M, Quesenberry CP, Zhou J, Whitmer RA. Heavy smoking in midlife and long-term risk of Alzheimer National and Kapodistrian University of Athens disease and . Arch Intern Med. 2011;171(4):333-339. 22. Zhong G, Wang Y, Zhang Y, Guo JJ, Zhao Y. Smoking is associated with an increased risk of dementia: a meta-analysis of Athens, Greece prospective cohort studies with investigation of potential effect modifiers. PloS One. 2015;10(3):e0118333. Taub Institute for Research in Alzheimer’s Disease and 23. Chen H, Huang X, Guo X, et al. Smoking duration, intensity, and risk of Parkinson disease. Neurology. 2010;74(11):878-884. 24. Ockene IS, Miller NH. Cigarette Smoking, Cardiovascular Disease, and Stroke: A Statement for Healthcare Professionals From the the Aging Brain, Gertrude H. Sergievsky Center American Heart Association. Circulation. 1997;96(9):3243-3247. Department of Neurology, Columbia University 25. Unger T, Borghi C, Charchar F, et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75(6):1334-1357. New York, NY 26. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336(16):1117-1124. 27. de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101-1113. Disclosures 28. Scarmeas N, Anastasiou CA, Yannakoulia M. Nutrition and prevention of cognitive impairment. Lancet Neurol. CZ, KS, JGH, and NS report no disclosures 2018;17(11):1006-1015.

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ONLINE-ONLY APPENDIX TABLE E1. COMMON PATIENT QUESTIONS AND SUGGESTED RESPONSES Common questions Suggested responses Patient resources Does my diet matter Yes, diet matters for overall health and can affect the health 2015-2020 Dietary Guidelines for Americans: if I am concerned of blood vessels in particular. There is increasing evidence of https://www.dietaryguidelines.gov/current- about developing a link between healthy blood vessels and dementia. Studies dietary-guidelines/2015-2020-dietary-guidelines dementia? of populations have found a link between certain healthy dietary patterns and lower risk for dementia.

It is reasonable to increase intake of certain food groups (eg, vegetables, fruits, nuts, etc.), and to consider adopting specific dietary patterns (eg, MeDi, DASH). Are there particular No, there is little to no evidence from clinical trials that GCBH-The Real Deal on Brain Health vitamins or specific vitamins or supplements significantly affect the Supplements supplements that I risk for dementia. It is possible that when whole foods are https://www.aarp.org/health/brain-health/glob- should take to pre- distilled into specific nutrients, benefits of other nutrients al-council-on-brain-health/resource-library/ vent dementia? are lost.

We recommend focusing on intake of specific foods and following a healthy dietary pattern, rather than intake of isolated micronutrients, in the form of supplements. What type of The jury is still out on what type of exercise, and what Physical Activity Guidelines for Americans, 2nd exercise is best for amount of exercise is optimal for maintaining brain health. edition (2018): brain health? There is some evidence that aerobic exercise may be https://health.gov/our-work/physical-activity/ particularly beneficial for cognition. current-guidelines

We recommend following the Physical Activity Guidelines for Americans (2018), which suggests at least 150 minutes of moderate-intensity aerobic activity per week, as well as strength training on 2 or more days per week. Should I start doing Education in early life helps to build cognitive reserve, GCBH-Recommendations on Cognitively crosswords or playing which allows the brain to better cope later on with a dis- Stimulating Activities Sudoku if I want to ease such as dementia. In later life, playing particular games https://www.aarp.org/health/brain-health/glob- prevent dementia? and practicing specific skills may improve performance on al-council-on-brain-health/resource-library/ specific tasks.

We do recommend continuing to participate in activities if they are enjoyable and remaining socially engaged, for psychological and other general health benefits. Is poor sleep related In the short-term, poor sleep can result in temporary GCBH-Recommendations on Sleep and Brain to dementia? thinking difficulties. Sleep apnea is a frequent cause of Health reversible cognitive impairment. https://www.aarp.org/health/brain-health/glob- al-council-on-brain-health/resource-library/ Whether chronic poor sleep can cause dementia is more debatable. Some studies suggest that chronic sleep problems increase the risk for dementia. Abbreviations: AASM, American Academy of Sleep Medicine; DASH, Dietary Approaches to Stop Hypertension; GCBH, Global Council on Brain Health; MeDi, Mediterranean diet; NIH, National Institutes of Health.

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ONLINE-ONLY APPENDIX Primary Prevention of Dementia

Modifiable Vascular Risk Factors Overweight (BMI 25 to < 30) or Obese (BMI > 30) Clinical Guidelines/Recommendations US Preventive Service Task Force Recommendations (2018; 2014) https://www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/uspstf-and-b-recommendations Recommend offering or referring all obese adults to intensive, multicomponent behavioral interventions (Grade B evidence) 1. Recommend offering or referring adults who are overweight or obese and have additional CVD risk factors to behavioral counseling to promote a healthful diet and physical activity (Grade B evidence) Resources for Patients 1. Centers for Disease Control and Prevention Adult BMI Calculator https://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/english_bmi_calculator/bmi_calculator.html 2. Centers for Disease Control and Prevention—Adult Obesity Causes & Consequences https://www.cdc.gov/obesity/adult/causes.html 3. MyPlate Phone App (set simple daily food goals, track progress) https://www.choosemyplate.gov/startsimpleapp

Physical Activity Clinical Guidelines/Recommendations Agency for Healthcare Research and Quality Systematic Review (2017) https://www.nap.edu/read/24782/ 1. Encouraging but inconclusive evidence that physical activity may delay or slow age-related cognitive decline 2. Insufficient evidence for whether physical activity prevents or delays clinical Alzheimer’s type dementia Resources for Patients 1. Physical Activity Guidelines for Americans, 2nd edition (2018) https://health.gov/our-work/physical-activity/current-guidelines 2. Centers for Disease Control and Prevention—Physical Activity While Social Distancing https://www.cdc.gov/physicalactivity/how-to-be-physically-active-while-social-distancing.html 3. Centers for Disease Control and Prevention—Adding Physical Activity to your Life https://www.cdc.gov/physicalactivity/basics/adding-pa/index.htm

Smoking Cessation Clinical Guidelines/Recommendations US Preventive Service Task Force Recommendations (2015) https://www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/uspstf-and-b-recommendations 1. Recommend asking all adults about tobacco use, advising cessation, and providing appropriate interventions (behav- ioral and pharmacotherapy for non-pregnant adults, and behavioral only for pregnant women) (Grade A evidence) Agency for Healthcare Research and Quality Guidelines for Smoking Cessation Pharmacotherapy https://www.ahrq.gov/prevention/guidelines/tobacco/prescrib.html 1. Special consideration should be given prior to pharmacotherapy with selected populations: those with medical contra- indications, those smoking less than 10 cigarettes/day, pregnant, and adolescent smokers 2. Firstline pharmacotherapies include: bupropion SR, nicotine gum, nicotine inhaler, nicotine nasal spray, nicotine patch

e2 PRACTICAL NEUROLOGY OCTOBER 2020 DEMENTIA INSIGHTS

Resources for Patients 1. Building a personalized quit plan https://smokefree.gov/build-your-quit-plan 2. QuitGuide phone app (track cravings, build skills) https://smokefree.gov/tools-tips/apps/quitguide 3. quitSTART phone app (provide tailored tips based on smoking history) https://smokefree.gov/tools-tips/apps/quitstart

Hypertension Clinical Guidelines/Recommendations US Preventive Service Task Force Recommendations (2018; 2014) https://www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/uspstf-and-b-recommendations 1. Recommend screening for high blood pressure in adults aged 18 years or older; recommend obtaining blood pressure measurements outside of the clinical setting for diagnostic confirmation before starting treatment (Grade A evidence) Agency for Healthcare Research and Quality Systematic Review (2017) https://www.nap.edu/read/24782/ 1. Encouraging but inconclusive evidence that blood pressure management for individuals with hypertension may pre- vent, delay, or slow clinical Alzheimer’s type dementia Resources for Patients 1. Centers for Disease Control and Prevention—Facts about Hypertension https://www.cdc.gov/bloodpressure/facts.htm 2. National Institutes of Health—Dietary Approaches to Stop Hypertension (DASH) Diet https://www.nhlbi.nih.gov/health-topics/dash-eating-plan 3. Centers for Disease Control and Prevention—Blood Pressure Medications https://www.cdc.gov/bloodpressure/medicines.htm

Other Vascular Risk Factors (Hyperlipidemia, Diabetes Mellitus, Other Cardiovascular Diseases Clinical Guidelines/Recommendations US Preventive Service Task Force Recommendations (2016, 2015) https://www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/uspstf-and-b-recommendations Recommend that adults without a history of cardiovascular disease use a low-to-moderate-dose statin for the prevention of cardiovascular events and mortality when all of the following criteria are met: 1) age 40 to 75 years 2) have 1 or more cardiovascular risk factors (i.e. dyslipidemia, diabetes, hypertension, or smoking) 3) have a calculated 10-year risk of a cardiovascular event 10% or greater (Grade B evidence) Recommend screening for abnormal blood glucose as part of cardiovascular risk assessment in adults aged 40 to 70 years who are overweight or obese (Grade B evidence) Resources for Patients\ Centers for Disease Control and Prevention—Know Your Risk for Heart Disease https://www.cdc.gov/heartdisease/risk_factors.htm Centers for Disease Control and Prevention—Preventing and Managing High Cholesterol https://www.cdc.gov/cholesterol/prevention-management.htm Centers for Disease Control and Prevention—Preventing Type 2 Diabetes https://www.cdc.gov/diabetes/prevent-type-2/index.html

OCTOBER 2020 PRACTICAL NEUROLOGY e3