Modifiable Risk Factors in Alzheimer Disease and Related Dementias: A Review

Abstract

Purpose:

Although Alzheimer disease and related dementias (ADRDs) have long been considered nonpreventable and even an inevitable consequence of aging, recent findings from longitudinal studies indicate a downtrend in age-adjusted incidence and prevalence of ADRDs in Western countries. This remarkable trend might be the result of improved management of so-called modifiable risk factors. The aim of this review is to present evidence of modifiable factors of ADRDs in a life-course approach.

Methods:

A PubMed database search was conducted between November and December 2020 to identify relevant studies evaluating the role of modifiable risk factors in the development of ADRDs. Key words (Alzheimer’s disease and modifiable risk factors) were used and specific inclusion and exclusion criteria applied.

Findings:

This review identifies modifiable factors for ADRDs divided into early-life, middle-life, and late-life risk factors, depending on the available window of preventive action. According to life course exposure, factors can be protective or deleterious for ADRDs that participate in the underlying pathophysiologic complexity of these diseases as well as the complexity for public health measures implementations.

Implications:

The available evidence derived from epidemiologic, preclinical, interventional studies suggest that modifiable risk factors for ADRDs offer opportunities for therapeutic and preventive actions.

Introduction

Alzheimer disease (AD) is the most common cause of dementia, affecting up to 20% of individuals >80 years of age. The number of patients with AD is predicted to exceed 7 million patients in 2030 and cost >$1 trillion to the US economy alone in 2050.¹ AD and related dementias (ADRDs) are characterized by a decline from a previously attained cognitive level that affects activities of daily living or social functioning, leading ADRDs to be the main causes of disability in elderly people, with a particularly high prevalence after 80 years of age.²

Longitudinal population studies have brought evidence of a downtrend in age-adjusted ADRD incidence and prevalence in high-income countries, although the total numbers of patients with ADRDs continue to increase because of the aging population.^3–6 This decrease has been associated with better and earlier management of modifiable risk factors, such as cardiovascular health, and higher levels of education.⁷ These findings suggest the role of modifiable risk factors in AD pathophysiology and advocate for continued work in primary prevention in the field of dementia management. This is particularly important in the absence of effective drugs to significantly change the course of AD. The acceptance of preventive measures in ADRDs is also the result of a conceptual shift toward the idea that neuropathologic hallmarks are present years before dementia onset. This begs the question, “Once plaque has begun to accumulate, can lifestyle changes modify the risk of transition to cognitive decline or can lifestyle changes affect the likelihood of the process beginning?” As ADRDs develop during a long preclinical period of possibly several decades, lifestyle factors during a person’s lifetime might reduce, or increase, an individual’s risk of developing ADRDs.

Increasingly, population-based, clinical, pathological studies have uncovered that the most common pathological presentation of dementia in community-dwelling elderly populations is not pure AD,⁸ and it is now widely acknowledged that most patients’ dementia likely has multiple causes. For example, the presence of small vessel disease attributable to lipohyalinosis of small arteries frequently coexists with AD neuropathological changes (amyloid plaques and neurofibrillary tangles).⁹ In addition, it has been suggested that vascular disease contributes to the severity of cognitive decline in AD.¹⁰ It still remains to be defined whether AD and small vessel disease in the brain are frequent comorbidities in the elderly population or whether a pathophysiological link exists between the 2 entities. Either way, this implies that patients could benefit from a variety of preventive measures.¹

The main focus of this review is the modifiable risk factors for ADRD. Briefly, nonmodifiable risk factors of ADRDs include age, gene polymorphisms, sex, race/ethnicity, and family history. The greatest risk factor for ADRDs is increasing age. Much research is centered on developing treatments that will delay aging and age-related diseases. Unfortunately, these treatments are still far from being available for use in the clinic. More than 20 genes are known to modify the risk of developing ADRDs. The first identified gene increasing the risk of AD was APOE, and it is still the strongest risk gene known. The newly identified genes by genome-wide association studies point at pathways implicated in the immune system and inflammatory responses, cholesterol and lipid metabolism, and endosomal-vesicle recycling.^1,11 Accounting for <1% of dementia cases and causing young-onset forms that develop before the age of 60 years, deterministic genes have also been identified. Finally, women are more likely to develop AD than men, even accounting for the fact that women typically live longer than men. The reasons for this remain unclear.

In this review, we discuss the current evidence about modifiable risk and protective factors for ADRDs derived from epidemiologic and interventional studies and analyze the opportunities for therapeutic and preventive interventions.⁸ ADRDs are multifactorial, complex conditions with several modifiable risk factors that can differentially affect risk, depending on the time of exposure within the life course. Therefore, this review presents different risk factors according to the age at which they most increase the risk of ADRDs (Table). We hope this life course approach will facilitate optimal lifestyle intervention strategies for different age groups and for individuals with different risk profiles.

Table 1.

Life course contribution of risk factors for Alzheimer disease and related dementias and their worldwide prevalence.

Factor	Risk Factor Prevalence Worldwide, %
Early Life (<45 Years of Age)
Less education	40
Middle life (45–65 Years of Age)
Hearing loss	31.7
Traumatic brain injury	12.1
Alcohol (>21 units/week)	11.8
Hypertension	8.9
Obesity (body mass index >30 kg/m2)	3.4
Anticholinergic drug use (in United Kingdom)	9.9
Later Life (>65 Years of Age)
Smoking	27.4
Physical inactivity	17.7
Depression	13.2
Social isolation	11
Diabetes	6.4

Most studies cited in this review were conducted and designed in high-income countries. Risks may differ in countries with differing sociodemographic characteristics. This is of particular importance (but beyond the scope of this review) because two-thirds of patients living with dementia in the world are in low-income countries.

Methods

This review article is based on a narrative literature review conducted using PubMed, which we first searched for the term Alzheimer’s Disease in combination with the terms modifiable risk factors and epidemiology and then subsequently for each identified modifiable risk factor in human research articles published in English since January 1, 2015. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. We largely selected publications from the past 5 years but did not exclude commonly referenced and highly regarded older publications. The search was conducted between November and December 2020. A narrative review summarizes different primary studies from which conclusions may be drawn. Results are of a qualitative rather than a quantitative nature and asserted to facilitate extended understanding within a field. We aimed to review literature from multiple sources and from diverse disciplines. The theoretical question facing our team was to determine whether risk factors of AD had been identified and whether their modification may be beneficial in AD; thus, the narrative review was performed accordingly and segmented according to the main modifiable risk factors we identified.

Results

Early-Life Factors

Lower educational attainment (fewer years of education) affects cognitive reserve and is considered a modifiable risk factor for ADRDs.⁷ With a prevalence of 40% worldwide, lower educational attainment, particularly lack of secondary school,⁷ is one of the most prevalent modifiable risk factors for AD. One of the first authors to introduce the notion of intellectual reserve was J. A. Mortimer.¹² Mortimer’s work was followed by a large-scale survey in China investigating the association between educational attainment and dementia.¹³ Since then, epidemiologic research has consistently reported that educational level is inversely correlated with the risk of developing ADRDs.^14–16 In the United States, for example, an observational cohort study of 21,057 participants found that higher educational level was associated with a lower risk of dementia (odds ratio, 0.42; 95% CI, 0.37–0.48). The risk of developing dementia decreased with the number of years of education (for >16 years of education: odds ratio [OR], 0.27; 95% CI, 0.21–0.35).¹⁷

Higher educational level could be a surrogate for other unmeasured variables and confounding factors, such as a direct effect on brain development and function, health behaviors and exposures, as well as the general health advantages of having more wealth and opportunities.¹⁷ An expansion of a minimum of high school education should be encouraged to decrease the incidence of ADRDs.

Notably, middle-life and late-life cognitive stimulation (in the forms of leisure cognitive activities) have also been associated with a reduced risk of dementia as reported by different population studies.^18,19 Of course, it is possible that changes in cognition preclude or decrease involvement in these types of activities, so their absence actually reflects a subtle change in cognition that might herald cognitive decline as suggested by a more recent study by Sommerlad et al.²⁰

Middle-Life Risk Factors

Cardiovascular Risk Factors

Several studies consistently reported an increased risk of dementia and AD in association with vascular and metabolic risk factors, such as hypertension, hypercholesterolemia, obesity at midlife, diabetes mellitus, and atherosclerosis.²¹ Recognition that dementia and other chronic diseases share several risk factors has led international bodies, such as the World Health Organization (WHO), to promote broad preventive efforts.² Evidence suggests that vascular pathological conditions promote the neuropathological hallmarks of AD.^22,23 For example, vascular insufficiency causing decreased cerebral blood flow is thought to activate Aβ cleavage and its accumulation. Abnormalities in the blood brain barrier caused by vascular disease are associated with inflammatory and immune responses, which can initiate neurodegenerative pathways.²⁴ Vascular risk factors are involved in the conversion from mild cognitive impairment (MCI) to AD²² because several studies have found that controlling vascular factors (such as hypertension and hypercholesterolemia) in patients with MCI delayed progression toward dementia.^25,26 In this section, we review the main findings for vascular factors and their associated risk of ADRDs.

Hypertension:

Hypertension is a treatable risk factor of ADRDs.^7,27 However, the association between blood pressure (BP) and ADRDs is complex. Midlife hypertension and later-life hypotension have deleterious effects on brain health.

Midlife hypertension (defined as a BP ≥140/90 mm Hg between 40 and 65 years of age) is associated with an increased risk of later-life ADRD in multiple longitudinal studies. The first study to describe this was the Honolulu-Asia aging study.²⁸ Risk of ADRDs was assessed in a cohort of 3703 Japanese American men who were categorized according to the presence of midlife hypertension. High systolic BP (≥160 mm Hg) was associated with increased risk of dementia in the untreated group (OR, 4.8; 95% CI, 2.0–11.8). This finding has been confirmed in subsequent longitudinal population studies.^29,30 However, in the Framingham and Whitehall studies cited above and others,^31,32 a later-life BP decrease was associated with increased dementia risk.

With regard to pharmacologic agents, evidence from observational studies indicates that antihypertensive drugs can reduce the risk of ADRDs.² These observations have been tested in randomized clinical trials, most recently by the Systolic Blood Pressure Intervention Trial–Memory and Cognition in Decreased Hypertension MIND trial³³ and the Heart Outcomes Prevention Evaluation 3 study,³⁴ with conflicting results. Nonetheless, a recent meta-analysis that included 12 trials with 92,135 participants concluded that BP lowering with antihypertensive agents was significantly associated with a lower risk of incident ADRDs during a mean follow-up of 4.1 years (OR, 0.93; 95% CI, 0.88–0.98).³⁵ The main effect observed is most probably attributable to the effect on the vascular component of dementia.

The current recommendations from the World Alzheimer Consortium recommend maintaining systolic BP at ≤130 mm Hg in midlife, stating that antihypertensive treatment is the only known effective preventive medication for dementia.³⁶ Optimal protective values for BP have yet to be defined for adults >80 years of age.

Hypercholesterolemia

The association between hypercholesterolemia and AD risk remains unclear and is probably complex.⁸ Similar to other vascular risk factors, this association could be partially explained by a survival bias and competing mortality associated with elevated cholesterol because of premature cardiovascular death. However, it has also been reported that unintended decreases in cholesterol levels in late life are indicative of ADRD risk rather than a protective factor.^37,38 This finding might be attributable to the localization of amyloid deposition in the arcuate nucleus and the hypothalamus, both brain areas of homeostatic regulation, or to the consequences of prodromal dementia, which affects olfactory function, increases apathy, and leads to decreased energy intake.

The 2 randomized clinical trials (Heart Protection Study and Pravastatin in Elderly Individuals at Risk of Vascular Disease [PROSPER] study) investigating effect of statins on cognition to date have rendered disappointing results.^39,40 The PROSPER study, for example, followed up 5804 individuals with high cardiovascular risk (70–82 years of age) and no diagnosed dementia for a mean of 3.2 years treated with pravastatin vs placebo. Cognitive function declined at the same rate in both treatment groups (with a Mini-Mental State Examination score difference of 0.06; 95% CI, −0.04 to 0.16; P = 0.26). Optimal target values for blood cholesterol among older adults are currently unknown, even with regard to cardiovascular disease prevention.²

Diabetes Mellitus

Diabetes is considered a lifelong risk factor for ADRDs (ie, both juvenile type I and adult onset type 2)² and is associated with an increased risk of ADRDs (1.5- to 2.5-fold).⁴¹ AD and diabetes mellitus share a number of common features, including increased prevalence after 65 years of age,⁴² high impact on quality of life, and associated increase in health care costs. The Rotterdam Study prospectively followed up a population-based cohort of 6370 elderly individuals (≥55 years of age) for a mean of 2.1 years and found that that the presence of diabetes at baseline almost doubled the risk of AD (relative risk [RR], 1.9; 95% CI, 1.2–3.1).⁴³ The pathophysiologic background for the role of chronic hyperglycemia in the development of ADRDs includes advanced glycation end product accumulation,^44,45 impaired insulin receptor activation with insulin-resistant state in the brain,⁴⁶ and direct glucose neurotoxicity.^7,47

Few interventional studies have investigated the effect of antidiabetic drugs on dementia outcomes, but a small meta-analysis that included studies with cohorts of patients with diabetes⁴⁸ reported that metformin reduced the prevalence of cognitive impairment (3 studies: OR, 0.6; 95% CI, 0.4–0.8) and reduced the incidence of dementia (6 studies: hazard ratio [HR], 0.8; 95% CI, 0.4–0.9). Intensive diabetic therapy and insulin therapy do not delay or improve cognitive decline, possibly because of the increased risk of hypoglycemia. The most recent International Guidelines for Diabetes Management⁴⁹ increase the glycated hemoglobin target based on global health and cognitive status of the patient. The question remains whether it is the increased frequency and severity of hypoglycemic episodes that increase cognitive decline or whether it is cognitive decline that complicates diabetes management and increases hypoglycemic events.

Obesity

Midlife obesity (defined as the prevalence of body mass index [BMI] >30 kg/m² between the ages of 35 and 64 years) affects >10% adults in the Western world.⁵⁰ Epidemiologic studies have confirmed an association between midlife BMI and the risk of developing late-life ADRD, which is independent of other vascular or socioeconomic risk factors.⁸ One metanalysis with a review of 19 longitudinal studies, including 589,649 participants 35 to 65 years of age with a follow-up of up to 42 years (mean of 23 years), found that obesity (BMI >30 kg/m²) was associated with late-life dementia (RR, 1.3; 95% CI, 1.1– 1.6).⁵¹ Additional evidence of the association is supported by results from patient autopsies and brain imaging studies. Obesity was linked to greater cortical atrophy in 700 patients diagnosed with AD or MCI with a 0.5% decrease in brain tissue volume (locally) for every unit increase in BMI.^52,53

Interestingly, and similarly to the reverse causality observed with BP and cholesterol levels in late life, BMI decreases in the years preceding dementia diagnosis and is considered by some to be a predictive sign for dementia.⁸ Unfortunately, no interventional studies with data about the long-term effects or the effect of weight loss before the age of 65 years in preventing dementia are available.

Smoking

Epidemiologic studies have confirmed that smoking is a risk factor for developing ADRDs, particularly for APOEe4 noncarriers.^7,36 The population-based follow-up Rotterdam Study, which included 6870 people 55 years and older and explored the effect of smoking on the risk of ADRDs, concluded after a mean follow-up of 2.1 years that smokers had an increased risk of developing AD (RR, 2.3; 95% CI, 1.3– 4.1).⁵⁴

The role of smoking in the development of cognitive impairment might be explained by the vascular disease correlated to smoking, but more recent studies also link the neurotoxins, such as various metals or various polycyclic aromatic hydrocarbons, present in cigarette smoke and tobacco plant to the increased risk of ADRDs⁵⁴ and increased at-risk biomarkers for AD.⁵⁵

A recent study explored passive smoking as a risk factor for ADRDs in 2037 women 55 to 64 years of age who had never smoked from the China Health and Retirement longitudinal study. They found that each additional year of second-hand smoke exposure added a 0.01-point decrease in score of memory in the follow-up (t score, −2.07; P < 0.05).⁵⁶ Finally, studies suggest that smoking cessation could prevent dementia cases because the risk of dementia is reduced to that of never smokers in people who have stopped smoking.^57,58

Other Midlife Risk Factors

Diet

Various nutrients and food items. such as ω3, polyunsaturated fatty acids, vitamins, and antioxidants, have been investigated for their potential protective role in ADRDs. Results have remained unconclusive, and research has shifted toward examination of dietary patterns.²

The Mediterranean diet (MeDi) (low intake of meat and dairy, high intake of fruit, vegetables, and fish, and moderate intake of alcohol) is the most studied diet for its protective role in ADRDs⁵⁹ (well reviewed by Yusufov et al⁶⁰). One of the first studies that explored the effect of the MeDi on the risk of AD was conducted in New York on 2258 healthy individuals (mean age, 76.5 years) prospectively followed up for 4 years. Higher adherence to the MeDi was associated with lower risk of AD (HR, 0.91; 95% CI, 0.83–0.98; P = 0.015) or 40% less risk for development of AD compared with lowest MeDi adherence.⁶¹

Unfortunately, evidence of a causal relationship between diet and reduced AD risk is still limited because of the small number of diet intervention studies conducted.

Dietary interventions can also include advice to eliminate or reduce certain high-risk foods such as advanced glycation end product–rich foods (particularly fats and proteins cooked at high temperatures)^45,62,63 or artificially sweetened drinks, associated with AD risk in a study.⁶⁴

The current WHO guidelines recommend a MeDi to reduce the risk of dementia because it might help and does not harm; however, WHO does not recommend any single-nutrient supplementation.⁶⁵

Traumatic Brain Injury

Increasing evidence has posited traumatic brain injury (TBI) as a risk factor for AD.²² The recent strong evidence led to the recognition of TBI as a convincing additional risk factor for AD.³⁶ TBI in nonveteran populations often happens during motor vehicle crashes or sports injuries, and preventive public health measures can be undertaken (eg, seatbelts or helmets). The greater the severity of the TBI and the higher the frequency, the higher the risk of developing ADRDs.^66,67 Two Scandinavian, longitudinal, observational population studies,^66,67 each of >3 million people >50 years of age, found an increased risk of dementia and AD risk with TBI. In the Danish study⁶⁶ the risk of AD was increased with a history of TBI (HR, 1.2; 95% CI, 1.2–1.3) and associated with the number of TBIs (1 TBI: HR, 1.2; 95% CI, 1.2– 1.3; >5 TBIs: HR, 2.8; 95% CI, 2.1–3.8). In the Swedish cohort, the increased risk of AD remained significantly elevated for >30 years of the follow-up (OR, 1.3; 95% CI, 1.1–1.4), albeit attenuated over time with the strongest associations in the first year after TBI (OR, 3.52; 95% CI, 3.23–3.84).⁶⁸

TBI is a recognized risk factor for AD. The prevention of TBI involves specific public health measures, such as requiring seatbelts and helmets and creating medical protocols for sports injuries, which are beyond the scope of this review.

Anticholinergics and Dementia

Drugs with anticholinergic properties inhibit the action of acetylcholine at its receptor, which centrally is involved in learning and memory.⁶⁹ Medications with anticholinergic properties (therapeutic or unintended) are commonly used in the geriatric population for diverse indications, including antihistamines, sleep agent, and treatments for overactive bladder. The prevalence of use in older adults is high,⁷⁰ considering the extensive and well-known side effect profile, which includes cognitive impairment. Some recent observational studies suggest that anticholinergics may be associated with a risk of developing dementia.^70–72

One prospective, population-based cohort study⁷⁰ of 3434 participants ≥65 years of age with no dementia found that higher cumulative anticholinergic use was linked to increased risk of all-cause dementia and AD. In this study, participants were followed up for a mean of 7.3 years, and 23.2% developed dementia, which was attributed to AD 80% of the time. A 10-year cumulative dose-response association was observed for dementia and AD (test for trend, P < 0.001).⁷⁰

A nested case-control study evaluated 58,769 British patients with a diagnosis of dementia and 225,574 controls ≥55 years of age. Evidence of prescriptions for 56 drugs with anticholinergic properties were used to measure the cumulative anticholinergic drug exposure.⁷⁰ The adjusted OR for dementia increased from 1.06 (95% CI, 1.03–1.09) in the lowest anticholinergic exposure category to 1.49 (95% CI, 1.44–1.54) in the highest category, compared with no anticholinergic drug prescriptions after adjustment for confounding variables identified as risk factors for dementia. These findings add further evidence of potential risks associated with anticholinergic drugs and highlight the importance of prescribing anticholinergic drugs with caution.

Hearing Loss

Hearing loss may be associated with increased risk of dementia, and fairly efficacious interventions are available.^7,36 Even though epidemiologic studies^73–75 have reported this link, the mechanism is not yet well understood. One systematic review⁷³ found that for the 17 included articles hearing loss was independently associated with a higher incidence of dementia.

A population-based cohort study⁷⁴ found that among 16,270 adult Taiwanese participants (divided into 3 age groups), 1868 developed dementia. During the follow-up period (mean [SD], 6.87 [3.36] years), the hearing loss group had an incidence of dementia higher than that in the non–hearing loss group (19.38 [95% CI, 18.25–20.57] per 1000 person-years vs 13.98 [95% CI, 13.01–15.00] per 1000 person-years) The link was higher in patients between 45 and 64 years of age (HR, 2.21; 95% CI, 1.57–3.12; false discovery rate P < .001).

In an interventional study following up a representative group of 2040 people >50 years of age for 18 years (mean, 14.4 years), there was less decline on immediate and delayed recall after hearing aid use was initiated. Hearing aid use was the biggest protective factor from cognitive decline (other protective factors were higher level of education, wealth, drinking alcohol, being female, and regular physical activities) (regression coefficient β for higher episodic memory, 1.53; P < 0.001) after beginning to use hearing aids.⁷⁶

Alcohol Consumption and Dementia

Studies suggest that the association between alcohol consumption and cognitive function depends on the frequency and amount of alcohol use.^77,78 In 2015, a systematic review evaluated 45 studies that found that dementia risk might decrease with light drinking (1–2 drinks a day) (RR, 0.72; 95% CI, 0.61–0.86) to moderate drinking (RR, 0.74; 95% CI, 0.61–0.91). Interestingly, in this study excessive late-life alcohol consumption did not affect the risk of AD (RR, 0.92; 95% CI, 0.59–1.45) and other dementias (RR, 1.04; 95% CI, 0.69–1.56).⁷⁹ Another systematic review synthesized the data on the epidemiology of alcohol-related dementia published between 1991 and 2016. Four studies reported that the proportion of dementia due to alcohol-related dementia in an early-onset dementia cohort was approximately 10%, whereas in late-onset dementia, it accounted for only 1.28%.⁸⁰ Another large cohort study of 31,624,156 patients admitted to French hospitals between 2008 and 2013 found a significant association between alcohol use disorders and dementia. In that group, 1,109,343 were diagnosed with dementia, with 5.2% having early-onset dementia. Of those early-onset dementias, 38.9% were alcohol related.⁸¹

In summary, studies on the association between alcohol consumption and AD are insufficient to date to create clear public health recommendations for limiting the risk of AD; however, excessive alcohol consumption is associated with a myriad of medical illnesses. Cultural and health-related factors and comorbidities make the establishment of this association challenging. Future prospective studies should take into account the frequency and amount of alcohol consumption as well as beverage type. Most studies rely on self-reported intake, which is often underreported.

Later-Life Risk Factors and Lifelong Factors

Physical Inactivity

Approximately one-third of the adult population in the United States, Europe, and the United Kingdom is physically inactive.⁶⁵ According to some studies,⁵⁰ physical inactivity could explain the largest proportion of AD cases in Western countries.

Several mechanisms could explain how physical activity could modify the pathogenesis of AD, such as reducing insulin resistance,^82,83 increasing brain glucose metabolism (P < 0.05),⁸⁴ reducing cytokine levels in the brain,⁸⁵ and stimulating neuro and brain plasticity.^83,86,87 Epidemiologic evidence supports the preventive effect of physical activity on the risk of AD, which is independent of the effects of a healthy diet⁸⁸ and conversely that low levels of physical activity are associated with a higher risk of developing AD. Individuals with lifelong exercise routines have larger brain volumes and improved executive function than inactive, age-matched, older adults.⁸⁹ Exercise also improves cognitive and functional symptoms. A total of 134 patients with AD performing a moderate exercise program for a year exhibited a significantly slower decline in the capability to perform activities of daily living (P = 0.02).⁹⁰ These results were confirmed by more recent studies in aging, MCI, and AD .^91–93

Current evidence suggests the potential protective and mitigating role of lifelong physical activity in AD. Additional randomized controlled trials studying the effect of exercise on the risk of developing AD are currently under way. Studies performed in patients with MCI seem encouraging and have led the American Academy of Neurology recently to issue a Level B (moderate confidence) recommendation for regular exercise in patients with MCI.⁹⁴

Depression

Depression, especially during late life, may either increase the risk of dementia or announce its prodromal stage. Despite a large number of observational studies and/or clinical trials, the association between late-life depression and dementia still remains unclear because of the complexity of this association.³⁶

Kaup et al⁹⁵ conducted a prospective cohort investigation of 2488 cognitively healthy, older adults with a mean (SD) age of 74.0 (2.8) who were 53.1% female and followed them up with repeated depressive symptom assessments from baseline to year 5. During this period, patients presenting with a dementia diagnosis were excluded. Incidence of dementia was monitored through year 11 of follow-up. Three depressive symptom trajectories were identified: consistently minimal or no symptoms (62.0%), moderate and increasing symptoms (32.2%), and high and increasing symptoms (5.8%). Compared with the consistently minimal trajectory, having a high and increasing depressive symptom trajectory was associated with significantly increased risk of dementia (fully adjusted HR, 1.94; 95% CI, 1.30–2.90).

Defining the timing of depression may be important to establish the nature of the association between depression and dementia. Singh-Manoux et al⁹⁶ conducted a 28-year (1985–2015) follow-up study (Whitehall II) in 10,189 persons, initially 35 to 55 years of age. Depressive symptoms were assessed on 9 occasions between 1985 and 2015 using the 30-item General Health Questionnaire. Retrospective analysis found that although early depression was not associated with dementia, those with chronic or recurring depression in the late phase (mean follow-up, 11 years) had a higher risk of dementia (HR, 1.67; 95% CI, 1.11–2.49). In fact, the dementia risk associated with depression was apparent 11 years before the dementia diagnosis but became 9 times larger in the year before the dementia diagnosis. This finding suggests that depressive symptoms might be a prodromal feature of dementia or that the 2 share common causes.

Although many studies are available, the association between dementia and depression remains unclear. There is strong evidence to support that development of depression toward the late stages of life is associated with an increased risk of development of dementia^95,96 either as an early sign or an accelerating factor.⁹⁷

Social Isolation

Social contact is now viewed as a protective factor against dementia.³⁶ Social isolation may occur as a prodrome of dementia. Some studies suggest social isolation increases the risk of dementia.

A 3-year follow-up study⁹⁸ suggested that feelings of loneliness but not social isolation predict dementia onset. This study tested the association among social isolation (living alone, without social support), feelings of loneliness, and incident dementia among 2173 community-living older persons without dementia. Those with feelings of loneliness were more likely to develop dementia (OR, 1.64; 95% CI, 1.05–2.56) than people without such feelings. Social isolation was not associated with higher dementia risk. In a study conducted by Poey et al⁹⁹ that examined whether the social environment moderates the association between the APOE e4 allele and cognitive function in 779 US adults ≥70 years of age, living alone (RR ratio, 5.814; P = .000) and self-reported loneliness (RR ratio, 1.928; P = .049) were associated with a greater risk of cognitive difficulty. Living arrangements, perceived social support, and loneliness were found to moderate the association between the APOE e4 allele and cognitive function.

The association between social isolation and development of dementia is complex and interrelated with other risk factors discussed in this review. For example, decreased executive function and depression, which seem to be associated with subclinical dementia, also feed into social isolation by limiting motivation and organizational ability to make plans and participate in activities. Focusing interventions to reduce social isolation for elderly populations may help tease out this complex association and may possibly act as a protective factor for dementia and other geriatric syndromes.

Multidomain Interventional Studies in Older Adults

Because the cause of ADRDs is multifactorial and has several potentially modifiable risk factors (as illustrated by this review), multidomain interventions that target several risk factors might be necessary for an optimal preventive effort.² Three large multidomain interventional trials have now been completed in Europe. The first completed study was the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. From 2009 to 2011, 1260 adults in Finland 60 to 77 years of age, with an elevated risk of dementia (as defined by a Cardiovascular Risk Factors, Aging, and Dementia Dementia Risk score >6), received coaching on diet, exercise, cognitive training, and cardiovascular risk management or only general advice on health. Surprisingly, people in both groups had cognitive improvements, probably because the control group had also received information enabling them to make some positive changes.¹⁰⁰ Further follow-up found that the group who received coaching had a 25% greater improvement in memory, mental-processing speed, and executive function. Even people with the APOE ε4 gene variant were able to benefit from the intervention.¹⁰¹ The 2 other multidomain interventional trials are the French Multidomain Alzheimer Preventive Trial¹⁰² and the Dutch Prevention of Dementia by Intensive Vascular Care trial.¹⁰³ Similar to the Finish study, first results were disappointing, but subsequent analysis in subpopulations remained encouraging.

Conclusions

ADRDs are multifactorial, complex conditions with many identified modifiable risk factors. However, large randomized controlled trials set up to prevent dementia (>250 participants per arm with a minimum of 6 months of follow-up) have only had modest or negative results, and in 2017 the National Academy of Medicine concluded that they were unable to endorse any specific public health recommendations for dementia prevention.

Key questions remain unanswered. For example, how, at which stage of the life course, and for how long any lifestyle interventions would need to be undertaken to address any of these risk factors. Most findings on modifiable risk factors are derived from observational studies that are limited in generalizability because there may be many unmeasured confounders. Similarly, reverse causation is an issue when using observational findings because, for example, social isolation, depression, and physical inactivity can increase in frequency among those who are becoming cognitively impaired.¹⁰⁴ Finally, although cardiovascular comorbidity at middle age is a risk factor for dementia, observational studies have found that vascular comorbidity in the oldest-old is no longer associated with incident dementia.¹⁰⁴

A final consideration includes the ethical implications of advocating prevention to individuals who are healthy and most of whom would never develop dementia. However, lifestyle interventions have minimal adverse effects and are beneficial to the individual regardless of their dementia risk¹⁰⁴ and in fact may improve other health or mental health metrics.

Identification of interventions that are effective and sustainable in different geographic, economic, and cultural settings should be the focus of future research. If ADRD modifiable risk factors can actually change the incidence of dementia, they could vastly improve quality of life for today’s and tomorrow’s older individuals and their families and in doing so would transform the future for society.