The Role of Vascular Risk Factors in Cognitive Impairment and Dementia and Prospects for Prevention

INTRODUCTION

Geriatricians and allied care providers are trained in the art of diagnosis and management of health-care problems in older persons. As specialists in the treatment of the elderly, geriatricians are frequently asked to evaluate older persons at risk for cognitive impairment or who may have existent mild cognitive impairment (MCI) or dementia.¹ As part of the diagnostic evaluation, clinicians are searching for reversible or treatable causes of cognitive impairment. Often overlooked is the importance of managing modifiable vascular risks that may negatively influence cognition.² Advances in clinical epidemiology have led to a primary care agenda for brain health largely based on the modification of vascular risks for the preservation of cognitive health.^3,4

This article discusses vascular risks as precursors to both vascular and nonvascular forms of cognitive impairment and dementia, their association with cognitive outcomes, and prospects for prevention.

Vascular Risks as Precursors to both Vascular and Nonvascular Types of Cognitive Impairment and Dementia

Over time we have seen a shift of emphasis in our understanding of cognitive disorders from the failure of cerebral function and cognition attributable to arteriosclerosis and reduction of cerebral blood flow to neurodegenerative mechanisms secondary to Alzheimer disease (AD), with recent shift in focus on vascular risks.^4-7 In fact, it was shown in the early 2000s that the absence of vascular risks was a predictor of healthy survival,⁸ and as vascular risks accrued according to the Framingham Stroke Risk Profile score, there was a stepwise loss of total cerebral brain volume accompanied by lower cognitive performance.⁹ In addition, vascular risks have been closely linked to both atherosclerosis and AD.¹⁰

With the publication of additional studies, the importance of vascular risks as potential precursors of the dementias has gained traction,^11-14and it has become apparent that midlife vascular risks such as hypertension are linked to an elevated risk of cognitive impairment and dementia later in life in both vascular and degenerative types of cognitive disorders. Furthermore, mixed neuropathology may be prevalent in older persons dying with cognitive impairment and dementia.^12,15

The increasing recognition of the role of vascular risks in defining brain health has resulted in significant initiatives focused on preventing or modifying vascular risks as a target to prevent or slow cognitive impairment and dementia.² In a seminal publication from an American Heart Association (AHA)/American Stroke Association work-group, optimal brain health in adults was defined according to AHA’s Life’s Simple 7 including 4 ideal health behaviors (nonsmoking, physical activity [PA] at goal levels, healthy diet according to current guidance, and body mass index [BMI] <25 kg/m²) and 3 ideal health factors (untreated blood pressure [BP] < 120/<80 mm Hg, untreated total cholesterol <200 mg/dL, and fasting glucose <100 mg/dL).² Support for a brain health initiative is bolstered by expert assessment of the evidence about potentially modifiable vascular risks by the National Academies of Sciences, Engineering and Medicine (NASEM) and the Lancet Dementia Commission, which are summarized in the “Clinics Care Points” section.^16-18

CLINICS CARE POINTS.

National Academies of Sciences, Engineering and Medicine (NASEM) Guidance¹⁶

Encouraging but inconclusive evidence for:

• Blood pressure management for persons with high BP to prevent, delay, or slow AD; and

• Physical activity to delay or slow age-related cognitive decline.

Additional research is needed as insufficient evidence exists for:

• Diabetes mellitus treatment;

• Dietary interventions;

• Lipid lowering therapy (eg, statins); and

• Vitamin B12 plus folic acid supplementation.

Lancet Dementia Commission on Prevention, Intervention, and Care Guidance¹⁸

Be ambitious about dementia prevention:

• Treat high BP in middle age (45–65 years) and in older persons (>65 years) without dementia to reduce dementia risk;

• Manage the following vascular risks for the potential to delay or prevent dementia cases: manage obesity in midlife, and smoking, physical inactivity, and diabetes mellitus in older persons.

Role of Key Vascular Risks

Hypertension

Hypertension has been established as one of the most important risk factors for stroke, with a population attributable risk of up to 50%.¹⁹ Hypertension has also been strongly linked with cognitive impairment and increased risk of dementia beyond symptomatic stroke.^20,21 The Atherosclerosis Risk in Communities was one of the largest population-based studies demonstrating the relationship between midlife hypertension and a 20-year decline in various domains of cognition.²² Midlife hypertension has been consistently linked with an increased risk of all-cause dementia, AD, and vascular dementia.²⁰ More recently, the relationship between higher BP levels, even in ranges below hypertension diagnosis guidelines, and worse cognition has been reported. For example, higher cumulative exposure to BP levels from early adulthood to midlife has been associated with worse cognition in midlife.^23,24 However, studies focused on hypertension during late life have often failed to find an association,^20,21 or reported nonlinear relationships where both high and low BP levels were correlated with cognitive decline.²⁰ Overall, a pattern of consistently raised BP during earlier adulthood to midlife followed by low BP levels in later life seems to negatively impact cognition.²⁵

Hypertension is often managed pharmacologically using antihypertensive medications. Although antihypertensive medications result in substantial benefits for cardiovascular morbidity and mortality, their role in improving cognition remains promising at best.^20,26 Results of well-designed, randomized clinical trials (RCTs) assessing the impact of various antihypertensive medications on cognitive outcomes are discussed in “Prospects for Prevention” section.

Diabetes Mellitus

Epidemiologic studies have demonstrated a clear link between diabetes mellitus, primarily type 2 diabetes (T2DM), and adverse cognitive outcomes.^27,28 T2DM is associated with lower performance in several cognitive domains²⁸ that likely start during the prediabetes stage and progress over time at a rate up to 2 times faster than normal aging.²⁷ T2DM has also been linked with an increased risk of MCI,²⁹ all-cause dementia,³⁰ vascular dementia,³⁰ and AD.³¹ The role of glycemic control—as measured by hemoglobin A1c (HbA1c)—in relation to cognition in T2DM remains unclear. Current evidence suggests either weak associations or evidence of nonlinearity where both low and high HbA1c relate to increased dementia risk in T2DM.^27,28 In contrast to T2DM, type 1 diabetes has been consistently linked with subtle decrements in cognition (or cognitive decrements) that likely develop soon after diabetes onset and follow a stable pattern over time or have only a slow rate of progression.²⁷ Risk factors associated with accelerated cognitive decline in diabetics include comorbid vascular risk factors, microvascular and macrovascular diseases, and depression.^27,28

Although the link between diabetes mellitus and cognitive dysfunction is clear, the effect of diabetes management in ameliorating dementia risk remains unclear. A Cochrane review on the effect of diabetes treatment on cognition did not find good evidence that any specific diabetes medication, or intensive versus standard glycemic control, prevented or delayed cognitive decline in patients with diabetes.³²

Obesity/Body Mass Index and Hypercholesterolemia

Obesity and body mass index

Epidemiologic studies have linked obesity to adverse neurocognitive outcomes, although findings are inconsistent across the life course. Generally, midlife obesity has been associated with a higher risk of dementia in later life, whereas late-life obesity has often been inversely associated with neurocognitive outcomes.³³ Pooled estimates from prospective studies suggest that midlife obesity (BMI ≥ 30 Kg/m²), but not overweight (25 < BMI < 30 kg/m²), confers 1.33 excess risk of dementia in later life.³⁴ However, late-life obesity and overweight (BMI 23–30 Kg/m²) have been associated with reduced risk of dementia by 25% and 21%, respectively.³⁵ At the same time, lower BMI and weight loss in older adults have been associated with an increased risk of dementia.³³ Such findings in older adults have been attributed to several biases, namely reverse causation bias.^33,36 Preclinical weight changes in years before dementia diagnosis has been estimated to result in 10% loss of body weight due to factors such as predementia apathy, loss of initiative, and decreased olfactory function.³⁷ Therefore, weight loss close to the diagnosis of dementia may underlie the preclinical phase of neurodegeneration.^36,37 Overall, midlife obesity and weight loss in later life seem to characterize the trajectory of BMI as it relates to dementia.³⁷

Many RCTs have assessed the effect of weight loss on cognition, although evidence on incident MCI and dementia is lacking. Pooled results from a meta-analysis of 7 RCTs showed that intentional weight loss improves memory over short periods (8–48 weeks).³⁸

Hypercholesterolemia

Higher cholesterol levels have been associated with adverse neurocognitive outcomes with inconsistent findings for midlife versus late-life studies. Although cholesterol measured in midlife has been generally linked with increased dementia risk in later life,³⁹ late-life studies show no or negative correlations.⁴⁰ Higher cholesterol levels in midlife followed by declining levels from mid-to-late life may characterize the life-course trajectory of cholesterol as it relates to dementia.²⁵

Hypercholesterolemia is often managed pharmacologically using statin medications. Although observational studies have suggested a relationship between statin use and reduced risk of dementia,²⁶ well-designed RCTs have failed to show cognitive benefit or harm associated with statin use.⁴¹ Therefore, current evidence does not support initiating statins in older adults to prevent cognitive decline but indirect evidence from observational studies may support their use in midlife to reduce dementia risk.²⁶

Cigarette Smoking

Evidence from experimental and epidemiologic studies suggests that cigarette smoking is associated with significant neurobiological and neurocognitive abnormalities.⁴² Tobacco smoking, especially in midlife, is a risk factor for late-life cognitive decline, all-cause dementia, vascular dementia, and AD.^43,44 Although some early studies suggested a protective effect of smoking on AD risk among the elderly, it has largely proven to be attributed to the bias in observational studies of late-life versus midlife individuals due to survival bias and competing risk of death.^45,46 Moreover, tobacco industry affiliation has been shown to play a significant role in early studies of smoking-related cognitive outcomes.⁴⁷ Smoking history has generally not been associated with increased dementia risk⁴⁴ but earlier smoking cessation may reduce dementia risk.⁴⁸ For example, recent smoking cession (<9 years) was associated with increased risk of dementia, whereas quitting smoking for 9 years or greater was not associated with increased dementia risk.⁴⁸

Physical Activity and Diet

Physical activity

Understanding the impact of PA on brain health is complicated because patterns of PA change according to age, sex, presence of comorbidities, and social and cultural factors.^18,49 Furthermore, baseline cognitive impairment and neurodegeneration could influence mobility, motivation, and goals for engagement in PA, hence, introducing bias in observational studies of PA and dementia risk.^49,50 To date, observational studies suggest that PA may be protective against adverse cognitive outcomes, whereas reverse causation bias cannot be excluded.⁴⁹ Overall, in nondemented individuals, high and low-to-moderate levels of PA have been shown to reduce the risk for cognitive decline by 38% and 35% compared with sedentary individuals.⁵¹ Among middle-aged adults, lack of midlife leisure-time PA is associated with a greater incidence of dementia during 14 years.⁵²

Pooled results from meta-analyses of RCTs on exercise training concluded that exercise improves cognition in adults aged older than 50 years, including those with MCI.¹⁸ Accordingly, exercise, especially aerobic exercise, may have a small but beneficial impact on cognition in cognitively normal individuals.²⁶

Diet

Dietary interventions prevent conditions that increase the risk for dementia, including diabetes and cardiovascular diseases.²⁶ A direct link between individual dietary components and neurocognitive outcomes has also been demonstrated. Such nutrients include fruits, vegetables, fish, polyunsaturated fatty acids, nuts, olive oil, and coffee.^26,53 However, during the last 5 years, research has moved toward studying overall diet composition and dietary patterns rather than individual dietary components.⁵³ Examples of these dietary patterns include the Mediterranean (MEDi) diet, Dietary Approaches to Stop Hypertension (DASH) diet, and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. Population-based studies have shown that higher adherence to these dietary patterns is associated with a reduced risk of dementia, AD, and cognitive decline.^53,54

Meta-analyses of RCTs on dietary interventions found no evidence for dietary supplements to preserve cognition or reduce dementia risk.^18,26 However, a meta-analysis of 5 RCTs found moderate evidence for the beneficial effect of the MEDi diet on global cognition in cognitively normal individuals.⁵⁵

PROSPECTS FOR PREVENTION: WHAT HAVE MAJOR CLINICAL TRIALS AND MULTIDOMAIN INTERVENTIONAL STUDIES TAUGHT US ABOUT VASCULAR RISKS?

Vascular risks are well known to be causal links for stroke, myocardial infarction, heart failure, and other cardiovascular diseases.² As such, the treatment or prevention of these factors, at the very least, will reduce the risk of cardiovascular disorders. An additional benefit of modification or prevention of vascular risks may be preserving brain health and preventing cognitive impairment and dementia.²⁰ In this section, we discuss interventional studies in relation to vascular risks and cognitive outcomes.

Studies Targeting 1 Key Vascular Risk

Systolic Blood Pressure Intervention Trial (SPRINT) and Memory and Cognition in Decreased Hypertension (SPRINT MIND).^56-59

Systolic Blood Pressure Intervention Trial (SPRINT) tested the effect of intensive systolic BP (SBP) lowering (target goal: <120 mm Hg) versus standard treatment (target goal: <140 mm Hg) on prevention of key cardiovascular outcomes.⁵⁶ Memory and Cognition in Decreased Hypertension (SPRINT MIND) is a companion study of SPRINT whereby the intensive SBP lowering strategy was tested among 9361 participants in relation to the primary outcome of probable dementia and the secondary outcomes of MCI and the composite of MCI plus dementia, respectively.⁵⁷

The main primary and secondary cognitive results of SPRINT MIND are listed in Table 1. Overall, the primary outcome, probable dementia, was not significantly different between the intensive versus standard treatment groups.⁵⁷ However, both secondary cognitive outcomes, MCI and the composite of MCI plus probable dementia, were significantly decreased by intensive BP lowering. In relation to magnetic resonance imaging biomarkers, intensive BP lowering therapy was associated with a smaller increase in cerebral white matter volume but a greater decrease in total brain volume.^58,59 It is important to note that the main phase SPRINT cardiovascular outcome study was stopped prematurely based on results favoring the intensive SBP lowering treatment.⁵⁶ As such the primary findings of SPRINT MIND must be considered in the context of a statistically underpowered outcome for probable dementia.

Table 1.

Main findings of SPRINT MIND

SPRINT MIND Demographics: Median Age = 67.9 y Percent Women Participants = 35.6%
Primary Outcome	Secondary Outcome	Brain Imaging Results
Probable dementia:  7.2 vs 8.6 cases per 1000 person-years for intensive vs standard BP lowering  HR: 0.83 (95% CI, 0.67–1.04	MCI:  14.6 vs 18.3 cases per 1000 person-years for intensive vs standard BP lowering  HR: 0.81 (95% CI, 0.69–0.95)	Intensive BP lowering was associated with a smaller increase in WM volume but a greater decrease in TBV. However, the differences were small
	Composite of MCI + probable dementia:  20.2 vs 24.1 cases per 1000 person-years for intensive vs standard BP lowering  HR: 0.85 (95% CI of 0.74–0.97)	b.Intensive BP lowering was associated with a greater decrease in HippV (consistent with the observation of greater decrease in TBV); however, other MRI brain biomarkers of AD were not significantly affected

Abbreviations: BP, blood pressure; CI, confidence interval; HippV: hippocampus volume; HR, hazard ratio; MCI, mild cognitive impairment; TBV, total brain volume; WM, white mater.

Data from Refs.^57-59

Earlier BP lowering trials did not show a significant positive signal for the preservation of cognition with BP lowering. A marginally beneficial signal for BP lowering on cognition was reported in 2 RCT.^60,61 A review of the individual trials is outside the scope of this article, and reviewed by the authors elsewhere.^20,62 In the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD MIND) trial, a companion study to ACCORD and similar to SPRINT, but for diabetic patients, there was no difference in relation to the intensive SBP lowering treatment versus standard treatment arm for verbal memory and executive function.⁶³ Furthermore, there was a statistically significant greater decrease in total brain volume at 40 months for intensive compared with standard SBP treatment.

Multidomain Interventions

It is argued that single vascular risk factor interventions may not be adequate to assure the prevention of cognitive impairment or dementia.^20,62 Therefore, it may be advantageous to administer multidomain interventions to modify vascular risks. One such study, Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), targeted diet, exercise, and cognitive training, and vascular risk monitoring, whereas the control group received counseling on general health.⁶⁴ The primary outcome was a change in cognition according to a comprehensive neuropsychological test battery (NTB), whereby there were between-group differences in the NTB scores annually of 0.022 (95% CL of 0.002, 0.042; P = .030) favoring the multidomain intervention group. In addition to improvement in overall cognition, there were significant benefits on executive function, processing speed, and BMI, dietary habits, and PA.⁶⁴ The promising results have led to a FINGERS worldwide network study to determine if the results can be validated in diverse populations. Other multidomain interventional studies are reviewed elsewhere.⁶² The latter studies have been less successful in relation to improving cognitive outcomes.

Other Interventions

As previously mentioned, there is insufficient evidence to conclude that the treatment of diabetes mellitus or lipids (eg, statin therapy), or administration of vitamins or other supplements or dietary modification definitively reduces the risk of cognitive impairment or dementia.¹⁶ In addition, there is no high level evidence that administration of low-dose aspirin (100 mg/d) is effective in preventing dementia, MCI, or cognitive decline.⁶⁵

Prospects for Prevention and Practical Guidance for Maintenance of Cognition and Brain Health

Of all the vascular risks, hypertension is the one factor with the largest body of observational epidemiologic and clinical trial study data in the context of brain health. Disparate and potentially flawed study designs across various RCTs have made it difficult to show a consistent and positive signal in relation to BP lowering and preservation of cognition.⁶² However, if one focuses on BP lowering trials of SBP lowering a 10 mm Hg or greater difference compared with the comparison group, it seems that one is more likely to find a beneficial effect of BP lowering on cognition.⁶⁶ Furthermore, there does not seem to be a preferred BP lowering medication class for cognitive maintenance suggesting that BP lowering may be the key factor rather than the class of medication.⁶⁷ Nonetheless, in a secondary analysis of SPRINT, antihypertensive medications that stimulated type 2 and 4 angiotensin II receptors compared with those that inhibit the receptors were associated with lower rates of incident cognitive impairment possibly by promoting beneficial effects on reduced brain ischemia, better blood flow, and improved memory.⁶⁸

SPRINT MIND provides the strongest evidence thus far in relation to intensive SBP lowering for maintenance of cognition, and FINGER provides the most promise for a multidomain approach to vascular risk factor control for preservation of cognition.^57,64 There remain, however, unanswered questions that we have reviewed elsewhere.^20,69 Of note, a recent publication from SPRINT suggests that intensive BP lowering when compared with standard BP lowering was associated with increased rather than decreased cerebral perfusion, especially among those with a history of cardiovascular disease.⁷⁰ There is a clear need for additional mechanistic studies in this domain.

Based on the above considerations, we provide the following guidance for BP control for the maintenance of cognition in older persons:²⁰

1. It is reasonable to lower BP to prevent cognitive impairment and dementia;⁷¹

2. The exact BP lowering target to maintain cognitive function remains uncertain; however, for persons who meet SPRINT MIND study eligibility criteria, it may be reasonable to aim for an SBP target of 120 mm Hg and follow SPRINT guidance on which BP lowering medications to administer;

3. For persons who do not meet SPRINT MIND criteria and who can tolerate SBP lowering, it may be reasonable to aim for an SBP target of 130 mm Hg or lesser, a national guidance target in the United States;⁷¹

4. For persons who have difficulty tolerating BP lowering because of the occurrence of adverse events, it may be reasonable to aim for an SBP target of 130 to 160 mm Hg, by titrating SBP control to the best tolerated SBP level; and

5. Management of other non-BP vascular risks is indicated to promote overall cardiovascular and possibly brain health.

SUMMARY

Epidemiologic studies have contributed key insights into the association between vascular risk factors and cognitive impairment across the life course. Hypertension is the one factor with the largest body of evidence. Current data suggest that hypertension as early as midlife serves as a predictor of cognitive impairment in later life. Midlife exposure to other vascular risk factors, including T2DM, obesity, hypercholesterolemia, smoking, physical inactivity, and an unhealthy diet, has been consistently linked with cognitive impairment in later life. However, findings from late-life studies have been less consistent, showing weak, nonlinear, or even inverse correlations. These inconsistencies have been attributed to biases inherent in observational studies. Therefore, RCTs provide a more definitive answer on the causal link between vascular risk factors and cognitive outcomes.

As more study data are being accrued, especially in the realm of RCTs, we suggest managing vascular risks according to national or international guidelines for the prevention of stroke and other cardiovascular diseases or preferentially according to those for the maintenance of brain health.^16,17,26 As new high-impact study results are published, practitioners will need to adjust the management of vascular risks according to the new findings. We anticipate that multidomain interventions will be required for preservation of brain health and cognition.

KEY POINTS.

• Vascular risk factors are precursors to vascular and nonvascular types of dementia.

• Modifiable vascular risk factors represent important targets for mitigating dementia risk among older adults.

• Clinical trials of intensive blood pressure lowering and those using a multidomain approach for the management of vascular risk have provided the most promising results for the preservation of brain health.