Chapter 

48

Focusing on the Effect of Body Mass Index

Status in the Risk of Vascular Dementia
Development
Mehmet Ilkin Naharci, MD and Huseyin Doruk, MD
Gulhane Medical Faculty Training Hospital, Etlik, Ankara, Turkey

LIST OF ABBREVIATIONS
VaD  vascular dementia
BMI  body mass index
VAT  visceral fat accumulation

INTRODUCTION
Dementia is a serious public health problem worldwide. As people age, the number of those suffering from dementia will
continually increase. By 2020, 42 million people are estimated to have dementia, with the incidence of 4.6 million per year
[1]. Dementia is a complex of syndromes that is characterized by deterioration in cognition and daily living activities and
by behavioral symptoms. Comorbid conditions are prevalent in demented subjects; in addition, dementia causes a twofold
increase in the mortality risk for people, irrespective of age, gender, and comorbidity [2].
Increasing evidence related to pathogenesis and pathophysiology of dementia emerge progressively; however, therapeu-
tic interventions remain to be ineffective generally. In recent years, the prevalence of dementia increases sharply with treat-
ment failure, even though medical science and the drug industry make vigorous efforts to prevent it. Therefore, the main
aim of management is primary prevention. The most important approach to primary prevention is identifying initial risk
factors. The elimination of preventable risk factors, using correct approaches as early as possible, will reduce the number
of patients with dementia.
Vascular risk factors are thought to accelerate cognitive decline in healthy individuals and worsen the clinical course of
patients with dementia. These factors can be divided into two groups, non-modifiable (age, sex, ethnicity) and modifiable
(hypertension, diabetes mellitus, hypercholesterolemia, atrial fibrillation, and smoking) [3]. There is growing evidence that
vascular risk factors, from an early stage of life, impair endothelial function of blood vessels in the brain and predispose to
cerebrovascular disease. Finally, this vascular pathology, namely atherosclerotic process, blocks the supply of blood to the
brain and leads to destruction of neurons. In fact, cognitive decline related to vascular risk factors appears to be indepen-
dent of the increase in stroke risk [3].
On the other hand, obesity is frequently accompanied by hypertension, diabetes mellitus, hyperlipidemia, inflammation,
thrombosis, and metabolic syndrome [4]. Obesity is known to cause insulin resistance, which is strongly associated with
vascular risk factors. Accordingly, obesity is characterized by low-grade chronic inflammation, resulting in endothelial dys-
function and accelerated atherosclerosis [5]. It was revealed that obesity and related factors contribute to the development
of cardiovascular pathologies, such as cerebrovascular, coronary, and peripheral vessel diseases [6].

THE REALITY OF VASCULAR DEMENTIA

Vascular dementia (VaD) is considered to be the second most common form of dementia after Alzheimer’s disease. The
disease is characterized by worsening memory and other cognitive areas, behavioral disturbances, and impaired functional

Diet and Nutrition in Dementia and Cognitive Decline.

© 2015
2012 Elsevier Inc. All rights reserved. 521
522 PART | II  General Aspects, Nutritional Factors, and Specific Conditions in Dementia and Cognitive Decline

abilities due to cerebrovascular disease and cerebral ischemia or hemorrhage. VaD may develop in acute or chronic process,
depending on the severity of damage or personal characteristics. It is well known that VaD is caused by reduced blood flow
to the brain, but in terms of definition and diagnostic criteria of this type of dementia a consensus has not yet been fully
achieved.
The prevalence of dementia over the age of 65 is estimated to be between 6% and 10%, and VaD is thought to build up
60% of patients with Alzheimer’s disease [7]. It was reported that the prevalence of VaD in the geriatric population ranges
from 0.6% to 2.1%, with a 2.52 cases per thousand annual incidence rate [8,9]. The prevalence of VaD in relation to age
shows a twofold increase in every 5–10 years, and it is more common in men [10]. Pure VaD is presumed to consist of 5%
and 20% of all dementia cases [11]. Post-stroke dementia is reported to occur with a rate of between 24% and 26.3% in
several clinical studies [12,13].
Factors related to VaD include demographic (advanced age, race and ethnic group, male sex, low status of education,
living in rural area), stroke (loss of cerebral tissue volume, infarct location and number), non-vascular (genetic, change in
hemostasis, heavy alcohol intake, aspirin use, physiological stress like depression or anxiety, eating habits, sedentary life),
and finally, perhaps the most important, vascular factors (hypertension, diabetes, smoking, heart disease, hyperlipidemia,
carotid bruits, menopause) [9]. VaD is implicated etiologically as a complex syndrome. Cognitive impairment is thought to
develop in this disease as a result of interactions between vascular diseases, demographic and environmental factors, and
cognitive reserve [7].

RELATION OF CHANGES IN BODY MASS INDEX TO VAD

Anthropometric measurements are used to estimate body composition. Body mass index (BMI) is calculated as body
weight divided by the square of height and closely correlated with body fat mass or fat percentage. BMI is a good indicator
of nutritional status. It has been increasingly recognized as a surrogate marker of adiposity and is practically used in poor
nutritional balance, such as under- or over-nutrition.
Recent epidemiologic studies have revealed that there is a statistically significant correlation between BMI and morbid-
ity-mortality rates of cardiovascular disorders, infections, and cancer. Therefore, there is an increase in studies that search
for the healthy BMI level, except for nutritional status assessment, in prevention and treatment of diseases [14]. In both
adults and the elderly, healthy diet, light alcohol consumption, no tobacco product use, regular exercise, and keeping exist-
ing comorbidities under control are interventions that could reduce future development of VaD [15,16]. However, in terms
of BMI, the situation is more complicated. It is thus critically important to reveal the quantitative relationship between the
categorized levels of BMI and VaD in the primary and secondary prevention of VaD.
To date, the underlying complex interactions between categorized levels of BMI and VaD have been poorly understood.
Such association is related to the specific pathological basis of this form of dementia and may provide strong support for
prevention efforts. New questions have emerged that have to be answered with care. First, is an overweight or obese adult
at increased risk of developing VaD in advanced age? Second, are low or high BMI levels and weight loss associated with
VaD in the elderly? In this section we will focus on studies examining the association between BMI and VaD.

Is Obesity in Midlife a Risk Factor for VaD in the Future?

Being overweight or obese in midlife is a well-known risk factor for cognitive decline and dementia in later life [17]. There
are certain studies that show structural changes in the brain related to this factor. It has been reported that global and central
midlife obesity has associations with subsequent trajectories of brain volume declines in total, frontal, and temporal gray
matter and orbito-frontal and cingulated gyri, and the precuneus in demented individuals, while it has a small effect on brain
atrophy in non-demented ones [18]. Another recent study has suggested that midlife overweight (RR = 2.53 (1.70–2.89))
and obesity (RR = 2.94 (2.44–3.03–2.89)) are significantly associated with increased risk of cerebral late life white matter
lesions [19]. With the emergence of publications showing the contribution of visceral adiposity in atherosclerosis, some
studies have demonstrated that visceral fat accumulation (VAT) has a prominent association with lower total and regional
brain volume rather than BMI [20,21]. In a sample of 733 middle-aged Framingham Offspring participants, Debette et al.
found an inverse association of BMI, VAT, waist circumference, and subcutaneous adipose tissue with total brain volume,
independent of vascular risk factors [20]. Also, the association between VAT and brain volume was the most significant and
was interestingly independent of BMI.
There are many prospective longitudinal studies that have evaluated the relationship of BMI in midlife to cognitive
decline or dementia, especially Alzheimer’s disease. But studies exploring the link between the risk of VaD in the future
and BMI in midlife are limited. In a sample of 10,136 adult participants who were re-examined an average 36 years later,
 Nutritional Status and Vascular Dementia  Chapter | 48 523

TABLE 48.1  The Risk Classification of VaD in

Midlife According to BMI Status
BMI Risk
Underweight Unknown
Normal Low
Overweight High
Obesity Very high

Underweight—BMI <18.5 kg/m2, normal—BMI 18.5–

24.9 kg/m2, overweight 25–29.9 kg/m2, obesity ≥30 kg/m2.
Abbreviations: VaD, vascular dementia; BMI, body mass
index.

being obese and overweight at midlife was found to have a 3.10- and 5.01-fold increased risk of VaD, respectively [22].
This excess risk of VaD was independent of stroke, cardiovascular, and diabetes mellitus. The metabolic cardiovascular syn-
drome (syndrome X) was reported to be associated with the increased risk of VaD in the Honolulu-Asia Aging Study with
a 26-year follow-up period. In this cohort study, Kalmijn et al. revealed that high BMI, skinfold thickness, and triglyceride
levels led to the increased risk of VaD in Japanese-American men [23]. The 2011 Nationwide Swedish Twin Study has sug-
gested that both overweight and obesity at midlife increase the risk of VaD, independently of diabetes and vascular diseases.
Xu et al. screened 20,206 individuals from the Swedish Twin Registry. Of those, 8,534 having information on height and
weight at midlife were examined to diagnose dementia patients, including those with VaD. In this cohort, having VaD was
related with 1.39 odds of being overweight and 4.38 odds of being obese at midlife [24]. Conversely, some prospective
studies did not find any association of midlife obesity and the risk of VaD. Fitzpatrick et al. in a prospective cohort study
of 2,798 community-dwelling adults, reported that midlife overweight and obesity were not associated with VaD when the
data are adjusted for demographics and cardiovascular risk factors [25]. Gustafson et al. studied the relationship between
BMI and the development of dementia subtypes, reporting that being overweight was not related to the incidence of VaD
[26]. These two studies had disadvantages of having low numbers of cases with pure VaD and shorter follow-up periods.
As a risk factor, the effect of midlife BMI on the development of VaD is supported by two meta-analyses. Actually, both
of the studies examined the association between Alzheimer’s disease, VaD, and any type of dementia and BMI at midlife
and late life. Analyzing only reported data on VaD, the first meta-analysis included three studies with a total of 20,476
participants and an average follow-up of 18.3 years. Overweight persons in midlife were found to have 33% increased risk
of VaD in the future as compared to those with normal weight [27]. A second meta-analysis and systematic review found
similar and appreciable results when obese adults ((RR = 5.01 (2.98–8.43)) were examined with follow-up time more than
10 years and baseline ages lower than 60 years [28].
Current evidence indicates that having BMI values above normal range in middle age is associated with increased risk
of VaD in the future. The risk classification of VaD in midlife according to BMI status is stated in Table 48.1. It may be
considered that vascular damage developed by underlying atherosclerosis caused loss of brain neuron cells in people living
with high BMI values from midlife. Intervention to prevent VaD must begin at an earlier age. An attempt to keep BMI
within normal range from midlife may be an effective treatment to reduce the risk of VaD.

Which Category of BMI in Later Life Would Be Related to VaD, Underweight or Overweight?
The increased prevalence of VaD in the elderly is focusing attention on preventive strategies and early detection. Focusing
on BMI in late life has provided some valuable data on its relation to VaD. Adipose tissue secretes a variety of hormones
that are involved in the regulation of food intake and energy homeostasis [29]. There are no published reports showing the
relationship of adipocytokines with VaD. Leptin, one of them, reduces food intake via entering into the brain and interacting
with the hypothalamus [29]. There are some possible mechanisms to discuss about the effect of leptin on cognitive decline
in patients with VaD. It was reported that obese people with higher plasma leptin concentrations had a reduced volume of
gray matter in the brain [30]. Overweight or obese subjects with leptin resistance may be prone to cognitive decline with
structural brain changes [31]. On the other hand, leptin deficiency may be harmful to maintenance and preservation of neu-
ronal plasticity [32]. New research is needed to clarify the relation between being underweight or overweight and VaD in
late life at the mechanistic level. Different levels or types of adipocytokines could explain this paradoxal relation.
524 PART | II  General Aspects, Nutritional Factors, and Specific Conditions in Dementia and Cognitive Decline

TABLE 48.2  Risk Factors for Cerebral Microbleeds Reported by

Yamada et al. [36]
Factors Odds ratio (95% CI)
Severe underweight 3.48 (1.06–11.4)
Intracerebral hemorrhage 7.06 (2.54–19.6)
Deep white matter hyperintensity 1.86 (1.15–3.01)

Severe underweight—BMI <17.0 kg/m2.

TABLE 48.3  The Risk Classification of VaD in Later Life

According to BMI Status
BMI Risk
Underweight Very high (especially for frail elderly)
Normal Intermediate
Overweight Low
Obesity Low

Underweight—BMI <18.5 kg/m2, normal—BMI 18.5–24.9 kg/m2,

overweight 25–29.9 kg/m2, obesity ≥30 kg/m2.
Abbreviations: VaD, vascular dementia; BMI, body mass index.

Accumulating evidence suggests that low BMI in late life is associated with cognitive decline and dementia [33,34].
However, there has been limited research on the association of BMI in late life and VaD. Underweight elderly persons were
found to have increased risk of VaD compared to those with normal BMI (HR: 2.15, 95% CI: 1.11–4.19) [25]. Hughes
et al. reported the results from the Kame Project, a cohort study of 1,836 Japanese Americans 65 years and older who were
followed between 1992 and 2001. Twenty-two VaD cases were diagnosed during the study period. Research showed that a
slower rate of decrease in BMI was associated with 63% reduction in risk of dementia. In addition, the authors concluded
that low BMI and a faster decline in BMI in late life resulted in increased risk of dementia in those who were initially over-
weight or obese [35]. In a 2012 study of 384 participants, the relationship between BMI and microbleeds in the brain diag-
nosed by MRI was investigated. Overall, BMI < 17.0 kg/m2 was found to have a significant risk of microbleeds in the brain.
Patients over 60 years of age with low BMI have had a significant excess risk for microbleeds (Table 48.2). Therefore, it
could be supposed that there is an association between microbleeds in the brain and VaD among those with low BMI [36].
There are few data on the association between high BMI and VaD in advanced age. In a cross-sectional study, we evalu-
ated 1,302 subjects and found that overweight and obese older persons had lower risk for cognitive decline as compared to
those with normal weight. One limitation of our study is that VaD cases were few (30 subjects); for this reason, we could
not perform a subgroup analysis for VaD risk [37]. A 2012 prospective study including 44,660 diabetic patients with a mean
follow-up period of 3.9 years has suggested that high BMI may be a preventive factor for dementia. Although VaD diagno-
sis was a primary end point of this study, there were no specific data on the association between BMI and VaD [38]. Anstey
et al., based on a meta-analysis of the effect of BMI on risk of dementia, documented that there was no association between
continuous late-life BMI and dementia, including VaD. But the authors added that shorter follow-up periods of late-life
studies may not be enough for evaluation of the risk of late-life BMI for dementia, and further data are required [27].
In late life, low BMI may be a risk factor for VaD, while high BMI is not. The risk classification of VaD in later life accord-
ing to BMI status is stated in Table 48.3. Cerebral microbleeds may contribute to the development of VaD in patients with low
BMI. Apart from a marker of malnutrition, low BMI in the elderly also could be a possible early clinical sign of VaD.

Is Weight Loss a Predictor of VaD?

Weight loss is a clinical condition that increases the morbidity and mortality risk in elderly [39]. The diagnosis of weight
loss, especially in the elderly population, is important to prevent or treat underlying causes because it may emerge at the
 Nutritional Status and Vascular Dementia  Chapter | 48 525

TABLE 48.4  Frailty Scale

1. ≥5% of unintentional weight loss in last year
2. Weakness: being in the lowest quintile for grip strength, adjusted for gender and BMI
3. Self-reported exhaustion
4. Slowed walking speed: being in the slowest quintile of the population, adjusted for gender and height
5. Low physical activity level: being in the lowest quintile for physical activity, adjusted for gender

Having three or more items is defined as frailty.

Abbreviation: BMI, body mass index.

(A) (B)

FIGURE 48.1  Horizontal sections of T2 weighted and flair MRI of a 74-year-old frail woman. She was referred to our hospital with cognitive
dysfunction, dysarthria, depression, appetite loss, weight loss (3 kg/3 months), and gait disturbance. (A) T2-weighted MRI showed multiple small lacunar
infarcts in both basal ganglions (arrows). (B) Flair MRI showed periventricular hyperintensities and white matter lesions (arrows). After a detailed medical
evaluation, she was diagnosed with VaD.

beginning or during the course of any disease. Little is known about the relation between weight-loss-related brain struc-
tural changes and VaD. Atherosclerosis could be a common biological link between weight loss and white matter lesions
[40]. These lesions are thought to impair fibers connecting frontal cortex and subcortical structures that are considered to
be important for executive functions [41]. Reduced food intake correlates with some deficits in executive functioning which
can be related to weight loss in elderly patients with VaD [41].
Frailty syndrome has been found to be a risk factor for VaD in the elderly [42]. Weight loss is one of the main criteria of
frailty syndrome (Table 48.4) [43,44]. Based on a sample of data of the Italian Longitudinal Study on Aging, Solfrizzi et al.
evaluated 2,581 participants aged 65–84 years with a 3.9-year median follow-up. The authors found that being frail was
associated with an 85% increased risk of overall dementia. The risk of VaD increased significantly, especially among frail
elderly people ((HR = 2.68 (1.16–7.17)) [42]. In another prospective cohort study, Three-City Study, 5,480 community-
dwelling elderly persons were followed with a mean 7 years of follow-up. There were 54 of VaD and 388 of all-cause
dementia cases. In this study, it is found that frail individuals have a greater risk of incident VaD (HR = 2.73 (1.05–7.13))
independent of all-cause dementia and vascular risk factors. Despite the small sample size of this study, it was prospective
and valuable in identifying cases of VaD in the follow-up period [43].
There are some reports that patients with cognitive decline show greater weight loss than those who have normal
cognition [44,45]. Gao et al. reported that subjects having overall dementia or mild cognitive impairment showed greater
decrease in BMI than those having normal cognition from 6 years before diagnosis [45]. This weight loss occurred in both
women and men. The authors remarked about some possible mechanisms for this relationship. They suggested that forget-
ting to eat, apathy, loss of initiative, impaired olfactory function, loss of taste, and difficulties in swallowing may explain
the underlying mechanism for this relationship [45,46].
Weight loss may predict VaD in the frail elderly (Figure 48.1). Atherosclerosis caused brain infarcts in some areas,
which may be the underlying pathophysiology of the relationship between weight loss and VaD. In the frail elderly patients,
therapeutic approaches must be applied both to prevent weight loss and brain infarcts caused by atherosclerosis.
526 PART | II  General Aspects, Nutritional Factors, and Specific Conditions in Dementia and Cognitive Decline

Delirium excluded
No Yes

Identifying of underlying conditions Dementia

No
Yes

Depression Sudden onset

Malignancy Stepwise deterioration of cognitive function
Arthritis Focal neurologic signs
Medications History of strokes

No Yes

Alzheimer disease
Vascular dementia
or other dementias

FIGURE 48.2  Evaluation of a frail elderly patient with cognitive dysfunction and clinically significant weight loss. Clinically significant weight
loss is defined as ≥2% decrease in 1 month or ≥5% decrease in 3 months or ≥10% decrease in 6 months.

PRACTICAL ISSUES
Taking into account a dramatic risk for functional disability, cognitive impairment, and mortality in VaD, there is increas-
ing interest on preventive and therapeutic strategies. Prevention is the preferable treatment for VaD, since there are no
conclusive data supporting the helpful effect of specific treatments. Strict control of vascular risk factors is very important
to prevent the development of VaD and the decline in cognitive status in earlier stages of the disease. Current evidence
indicates BMI status as a modifiable factor to influence the development of VaD. Because stroke is well defined and is a
common potentially modifiable risk factor for VaD, it should be clarified as the underlying mechanism between stroke and
BMI status. Unfortunately, few studies have evaluated the association between BMI status and the risk of VaD. It can be
said that similar studies were done more with Alzheimer’s patients.
A comprehensive intervention in older adults having weight loss or low BMI has a beneficial effect on the prevention and
progression of VaD. If the subject is frail, this intervention adds even greater benefit in terms of decreasing morbidity and
mortality. Higher BMI above normal range in midlife seems to have an influence on the future VaD risk, and therefore it is
helpful to attempt conventional weight reduction approaches to this high-risk group such as diet, physical activity, and behav-
ior therapy. Further research will be required to fully explore the underlying pathophysiological changes in the association
between BMI status and VaD and to determine how useful clinical implications are in the prevention and progression of VaD.

SUMMARY POINTS
● VaD is the second most common form of dementia after Alzheimer’s disease.
● There are still limited evidence and recommendations on preventive and therapeutic measures to be taken for VaD.
● Higher BMI (>25 kg/m2) in midlife appears to increase the development risk of VaD in the future.
● BMI (<20 kg/m2) may be considered as a possible early sign of VaD in the elderly.
● Clinically significant weight loss seems to occur in frail elderly patients with VaD (Figure 48.2).

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