An estimated 44 to 47 million people are living with dementia worldwide.¹ Dementia is a significant cause of morbidity and mortality among the aging population,¹ with high economic costs and significant burden on caregivers.² No disease-modifying treatment for dementia yet exists. Although primary prevention remains an elusive goal, modifiable risk factors may account for up to 35% of the dementia burden.³

The study of lifestyle factors and dementia risk is inherently challenging because of residual confounding in observational studies and attrition in clinical trials of lifestyle interventions. Although there is insufficient evidence to establish public health guidelines for primary prevention of dementia,⁴ the extant epidemiologic evidence justifies counseling patients to make lifestyle changes both for global health benefits and potential dementia risk modification.

In this selective review we aim to provide an update of current knowledge on primary prevention of dementia with a practical focus on counseling patients on making relevant lifestyle modifications. Specifically, we focus on clinical management of comorbidities (vascular risk/protective factors), counseling on diet, cognitive activities, and sleep. We also offer suggestions for fielding common questions on the relationship between lifestyle factors and dementia risk.

Vascular Factors

By some estimates 90% of stroke is preventable.⁵ Stroke is an independent risk factor, approximately doubling dementia risk, and mixed pathologies are common.^6,7 Stroke and dementia likely share some modifiable risk and protective factors.⁸ Considering this evidence, the World Stroke Organization’s call for the joint prevention of stroke and dementia has been endorsed by 23 international, regional, and national organizations, including the American Academy of Neurology.

Overweight or Obesity

Obesity is associated with myriad neurologic consequences, including increased stroke risk,⁹ poor cognition and dementia, autonomic dysfunction, and polyneuropathy.¹⁰ Consistent with recommendations from the American Heart Association and the American College of Cardiology, the US Preventive Services Task Force (USPSTF) recommends all obese adults be offered or referred to intensive multicomponent behavioral interventions. Behavioral counseling to promote a healthy diet and physical activity is recommend for adults who are overweight or obese and also have cardiovascular risk factors.¹⁰ Overweight and obese participants in 1 study had nearly twice the odds of reporting a 5% weight loss in the past year if their physicians merely informed them they were overweight. Furthermore, these patients had more than twice the odds of reporting more than 10% weight loss if their physicians had actively discussed their weight status.¹¹ Another study found that individuals diagnosed as obese or overweight by a healthcare provider were more likely to pursue lifestyle changes to control their weight.¹² Considering the significant impact of obesity on neurologic outcomes, it is reasonable for the neurologist to discuss weight status with patients.

Physical Activity

Physical activity promotes recovery after ischemic insult, and neuronal survival after neurotoxic injury in animal models. Insulin-like growth factor is a potential mediator of these neuroprotective effects.¹³ Physical activity also promotes brain maintenance, builds cognitive reserve, and may even reduce accumulation of brain pathology.^14,15 The World Health Organization recommends 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity aerobic activity per week for adults ages 18 to 64 and suggests additional benefits from doubling the weekly duration of activity. Muscle strengthening activities on 2 or more days a week are recommended.¹⁶ Stated goals for these recommendations are to improve cardiorespiratory and muscular fitness and bone health and reduce the risk of noncommunicable diseases and depression. These recommendations are essentially identical to the 2018 Physical Activity Guidelines for Americans (PAG),¹⁷ although the WHO recommends aerobic activity periods last at least 10 minutes, whereas US PAG suggests small increases in physical activity (eg, parking further away) may still be of benefit.

What amount of activity is needed to benefit the brain, however, remains unclear. A recent randomized clinical trial found that 6 months of aerobic exercise (40 to 55 min/session in 4 sessions/week) improved executive function among adults age 20 to 67, with a stronger effect observed in adults more than age 38.¹⁸ These results are consistent with a previous trial showing a 1-year aerobic exercise intervention selectively increased anterior hippocampal volume by 2%, offsetting the annual 1% to 2% volume loss associated with aging.¹⁹ A systematic review of 19 randomized clinical trials (most lasting <1 year) concluded there is encouraging but inconclusive evidence that physical activity may delay or slow age-related cognitive decline and insufficient evidence of whether physical activity prevents or delays clinical Alzheimer-type dementia.⁴

Smoking

Smoking doubles stroke risk in a dose-dependent relationship in which every 5 additional cigarettes per day increases stroke risk 12%.²⁰ Studies on the association between smoking and dementia, however, have found varying results. Some have employed short follow-up times, and other studies that have examined smoking in midlife were conducted in homogenous populations. A large study in a multiethnic cohort with a mean follow-up period of 23 years found an association between heavy smoking during midlife and increased long-term dementia risk.²¹ A meta-analysis found current smokers have 30% increased dementia risk, although survivor bias and competing risks likely make this an underestimation of effect size.²² Of note, epidemiologic studies have consistently found an association between smoking and decreased risk of Parkinson disease.²³ Further research is needed to elucidate the biological mechanisms underlying this relationship. The USPSTF recommends clinicians ask all adults about tobacco use.¹⁰ Providing minimal intervention by simply asking about smoking and recommending cessation can be valuable.²⁴ Smokefree.gov is a useful resource that provides targeted smoking cessation resources to address the needs of specific populations, including women (notably pregnant women), people in their teens or over age 60, veterans, and Spanish-speakers.

Hypertension

In the SPRINT trial,^a intensive vs regular blood pressure control (systolic blood pressure [SBP] <120 mm Hg vs 140 mm Hg) did not significantly reduce probable dementiarisk but did reduce the risk for mild cognitive impairment (MCI). Positive evidence from prospective cohort studies and mixed results from randomized clinical trials provide encouraging but inconclusive evidence that blood pressure management for hypertension may prevent, delay, or slow clinical Alzheimer-type dementia.⁴ The USPSTF is updating 2015 recommendations to screen for high blood pressure in adults age 18 years or more.¹⁰ Lifestyle modification is the first line of antihypertensive treatment,²⁵ and the Dietary Approaches to Stop Hypertension (DASH) diet is effective in treating hypertension with an effect size comparable to drug monotherapy.²⁶ Hypertension can also be secondary to comorbid conditions (eg, obstructive sleep apnea) that may be reversible causes of cognitive impairment and should not be missed during the neurologic assessment.

Similar considerations apply for screening and management of other vascular risk factors, including hyperlipidemia and diabetes. In particular, there is evidence that impaired insulin signaling occurs in the early stages of cognitive impairment, leading some to propose that Alzheimer disease may represent “type 3 diabetes.”²⁷ There is currently insufficient evidence (because of too few randomized controlled trials) to determine the effectiveness of lipid-lowering treatment (statins) and diabetes treatment for preventing age-related cognitive decline or clinical Alzheimer type dementia; both are recognized priorities for future research.⁴ Clinical guidelines and recommendations for management are provided for each vascular factor in the supplemental interactive Appendix in the online version of this article. Our interpretation of how to use this information is summarized in Box 1.

Diet

There are multiple ways to examine the relationship between diet and cognitive outcomes. Studies have focused on individual micro- and macronutrients, food groups, and dietary patterns. Most studies of specific nutrients or diet are observational (Tables 1-3), although some notable clinical trials of B vitamins, antioxidants, and fatty acids have largely observed no significant effect with a few showing protective effects.²⁸ Studies of food groups have been almost entirely observational, with the notable exception of some clinical trials on olive oil and seeds intake.²⁸ Overall, the evidence is stronger for an association between dietary patterns and cognitive outcomes, than for individual nutrients or food groups and cognitive outcomes.^28,29

The Mediterranean diet (MeDi) is the best studied dietary pattern, consisting of high intake of vegetables, legumes, fruits, and cereals; moderate intake of fish; low intake of meat and poultry, and low-to-moderate intake of dairy products. Moderate alcohol intake, generally during meals, is part of MeDi, as is high intake of unsaturated fatty acids (eg, olive oil) with low intake of saturated fatty acids. DASH is another well-studied dietary pattern that is high in vegetables and fruits and low in fat. DASH has been shown effective in decreasing blood pressure, both in hypertensive and prehypertensive individuals. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet is a hybrid of the MeDi and DASH diet focused on plant-based foods and limited intake of saturated fat, specifying consumption of green leafy vegetables and berries, and not specifying high fish, fruit, or dairy intake. The US Dietary Guidelines (2015-2020) recommend the MeDi, DASH, and a vegetarian diet as examples of healthy eating patterns.³⁰

Based on available data, it is reasonable to counsel patients to increase intake of particular food groups, including vegetables, fruits, fish, olive oil, and nuts. Depending on patient preference, we recommend providing examples of healthy dietary patterns (eg, MeDi) that are described in the US Dietary Guidelines (2015-2020). It should be noted that lifestyle behaviors may confound the study of dietary patterns. For example, studies of MeDi have not typically accounted for other aspects of the Mediterranean lifestyle such as sharing meals, length of meals, and siestas.³¹ With careful attention to study design, it may be possible to tease out the effects of diet, independent of these confounding factors.

Caloric restriction extends lifespan in animal models and holds promise as a potential intervention in humans. In the first human clinical trials of calorie restriction, 2 years of moderate calorie restriction significantly reduced cardiometabolic risk factors in young nonobese adults. These findings are consistent with observations collected from members of the Calorie Restriction Society, who have been voluntarily restricting caloric intake to ~1800 kcal/day for an average of 15 years, while maintaining optimal nutrition.³² Further studies are needed before caloric restriction can be safely recommended to patients as a viable lifestyle modification (Box 2).

Cognitive Activities

Observational studies suggest that cognitive activities may enhance cognitive reserve,¹⁴ which compensates for both age-related brain changes and pathologic changes of dementia. Although education in early life builds cognitive reserve, individuals with higher educational and occupational attainment may exhibit more rapid cognitive decline.³³ This could be because highly educated individuals compensate better for mild symptoms and do not present until more severe symptoms present along with a higher level of neuropathology. There is encouraging but inconclusive evidence that cognitive training may delay or slow age-related cognitive decline but no evidence that cognitive training reduces the risk of clinical Alzheimer-type dementia in individuals with normal cognition or MCI.⁴ These conclusions were drawn largely from a single large randomized trial (n=2,802) of cognitive training in community-dwelling adults more than age 65.³⁴ In this trial, cognitive training had long-term (10-year) effects on self-reported maintenance of instrumental activities of daily living (ADLs), but training effects on specific cognitive abilities dissipated slowly over time. Consensus recommendations from the Global Council on Brain Health (GCBH)³⁵ suggest cognitively stimulating activities over the life course (including formal or informal educational activities) provide benefits to adult brain health. There is evidence that participation in leisure activities is associated with reduced dementia risk independent of education level.³⁶ If patients enjoy particular mentally stimulating activities such as Sudoku, particularly if these activities involve social interaction, they should be encouraged to continue those activities.

Sleep

Observational studies show consistent associations between sleep-disordered breathing and cognition.³⁷ Compared with other modifiable lifestyle risk factors, however, modifying sleep patterns and disorders is challenging. Although treatment of sleep apnea is relatively straightforward, adherence to treatment can be challenging. Treatment for other sleep disorders (eg, insomnia, REM sleep behavior disorder, circadian rhythm dysfunction) varies considerably. Exercise is associated with better sleep in epidemiologic studies, although reverse causation is possible.³⁸ To our knowledge, there are no randomized controlled trials on sleep interventions for the primary prevention of dementia yet, making it unclear whether poor sleep precedes dementia as a potential modifiable risk factor or is a consequence of dementia.

Biologically, several mechanisms related to sleep dysfunction could potentially lead to developing dementia. Chronic intermittent hypoxemia could lead to microvascular changes and subsequent cognitive impairment.³⁷ The sleep-wake cycle regulates glymphatic clearance, and sleep deprivation may decrease amyloid clearance.^39-41

It has been suggested that screening for sleep-disordered breathing should be included in the clinical evaluation of cognitive impairment in adults.⁴² The GCBH 2017 consensus lists chronic inadequate sleep as a risk for more severe dementia. This consensus also notes that although sleep quality changes with aging, persistent daytime sleepiness is not part of normal aging, and behavior change to improve sleep is possible at all ages (Box 3).⁴³

Conclusion—Fielding Questions from Patients

When discussing lifestyle factors and risk for dementia with patients, we suggest an evidence-based approach tailored to the individual patient’s needs without rigid adherence to consensus recommendations. The study of lifestyle factors and dementia risk is fraught with methodologic difficulties. It is important to keep these limitations in mind when interpreting the evidence. For a list of common questions from patients and our suggested possible responses, see Table e1 in the online version of this article.

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)

1. Recommend offering or referring all obese adults to intensive, multicomponent behavioral interventions (Grade B evidence)
2. 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
2. Centers for Disease Control and Prevention—Adult Obesity Causes & Consequences
3. MyPlate Phone App (set simple daily food goals, track progress)

Physical Activity

Clinical Guidelines/Recommendations

Agency for Healthcare Research and Quality Systematic Review (2017)

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)
2. Centers for Disease Control and Prevention—Physical Activity While Social Distancing
3. Centers for Disease Control and Prevention—Adding Physical Activity to your Life

Smoking Cessation

Clinical Guidelines/Recommendations

US Preventive Service Task Force Recommendations (2015)

1. Recommend asking all adults about tobacco use, advising cessation, and providing appropriate interventions (behavioral 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

1. Special consideration should be given prior to pharmacotherapy with selected populations: those with medical contraindications, 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

Resources for Patients

1. Building a personalized quit plan
2. QuitGuide phone app (track cravings, build skills)
3. quitSTART phone app (provide tailored tips based on smoking history)

Hypertension

Clinical Guidelines/Recommendations

US Preventive Service Task Force Recommendations (2018; 2014)

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)

1. Encouraging but inconclusive evidence that blood pressure management for individuals with hypertension may prevent, delay, or slow clinical Alzheimer’s type dementia

Resources for Patients

1. Centers for Disease Control and Prevention—Facts about Hypertension
2. National Institutes of Health—Dietary Approaches to Stop Hypertension (DASH) Diet
3. Centers for Disease Control and Prevention—Blood Pressure Medications

Other Vascular Risk Factors (Hyperlipidemia, Diabetes Mellitus, Other Cardiovascular Diseases

Clinical Guidelines/Recommendations

US Preventive Service Task Force Recommendations (2016, 2015)

1. 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:
   • age 40 to 75 years
   • have 1 or more cardiovascular risk factors (i.e. dyslipidemia, diabetes, hypertension, or smoking)
   • have a calculated 10-year risk of a cardiovascular event 10% or greater (Grade B evidence)
2. 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

1. Centers for Disease Control and Prevention—Know Your Risk for Heart Disease
2. Centers for Disease Control and Prevention—Preventing and Managing High Cholesterol
3. Centers for Disease Control and Prevention—Preventing Type 2 Diabetes