Abstract
Objective
To examine the association between body mass index (BMI) and cognitive decline (CD) due to Mild Cognitive Impairment (MCI), Alzheimer's Disease (AD), and Vascular Dementia (VaD).
Design and setting
The subjects aged ≥ 65 years were recruited prospectively from the Geriatrics Clinic of Gulhane Medical School, between 2004 and 2008 years.
Participants
1302 patients were included in the study.
Measurements
Cognitive status, clinical diagnosis of CD (MCI, AD, and VaD) and clinical and environmental risk factors were evaluated by comprehensive geriatric assesment. Finally, the subjects were categorized into two groups according to having CD or not.
Results
905 (69.5%) subjects were not having CD whereas 397 (30.5%) patients with CD. Of the patients with CD, 140 (10.4%) had MCI, 227 (16.9%) AD, and 30 (2.2%) VaD. After adjustment for confounding with a model for multiple regression analysis, age (OR=1.054; CI:1.027–1.083; p<0.001) and family history of dementia (OR=1.662; CI:1.038-2.660; p=0.034) were found to be independent risk factors for CD. Also, overweight (OR=0.594; CI:0.370–0.952; p=0.03) and obese (OR=0.396; CI:0.242–0.649; p<0.001), and high education level (OR=0.640; CI:0.451-0.908; p=0.012) were found to be independent protective factors for CD.
Conclusions
We found the risk of CD decreases in overweight and obese elderly. The results indicate that the primary prevention should not only consider risk factors, but must also take anthropometric data into consideration in order to identify persons at high risk for CD.
Key words: Cognitive decline, body mass index, elderly
Introduction
The number of people suffering from dementia is sharply increasing, calling for actions from the health care system and society. Thus, dementia emerges as one of the most significant public health problems. Alzheimer's Disease International has reported that there are currently 30 million people with dementia in the world, with 4.6 million new cases annually (1). Since there are limited effective treatments for dementia, the main goal of the management is primary prevention. The identification of the risk factors for dementia appears to be the best approach for primary prevention. The elimination of the preventable risk factors, in early time using the proper strategies, can decrease the number of patients suffering from dementia.
Age, family history of dementia, female sex, and low education level are factors that raise the incidence and prevalence of dementia and, specifically, Alzheimer's Disease (AD) (2). In the past decade, it was demonstrated that several vascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and atherosclerosis play a part at the cognitive decline (CD), especially in elderly.
High blood pressure in middle-age, for example, is a clear risk factor for dementia in old age (3, 4), however, in advanced age, it was reported that low blood pressure might related with an increased risk of dementia (5, 6, 7, 8). In addition, the association between body mass index (BMI) and dementia may vary in different periods of life. In a prospective cohort study, high mid-life BMI was independently associated with CD at follow up (9). However, Chu et al. suggested that low late-life BMI and waist circumference represent potentially useful preclinical markers for Mild Cognitive Impairment (MCI) and AD (10). Some studies indicated that weight loss precedes the diagnosis of dementia (11, 12). Regarding to pathophysiological mechanism, it is not clear whether high BMI, alone or as an part of metabolic syndrome, might cause to dementia or not.
This study aimed to examine the relationship between BMI and CD due to MCI, AD, and Vascular Dementia (VaD). The secondary aim of the study was to determine the association between several factors including socio-demographic, psychosocial, and cardiovascular factors and CD.
Methods
All patients (aged = 65 years) were recruited prospectively from the Geriatrics Clinic of Gulhane Medical School, between 2004 and 2008 years. The subjects were given an information sheet, and written informed consents were obtained from either themselves or one of their representatives including spouses and adult children. The study was approved by the ethics committee of the Gulhane Medical School.
The analysis was carried out on 1521 subjects. Other dementias out of AD and VaD (n=92) were excluded from the study. Fifty-nine subjects were excluded because of incomplete data. Twenty-one subjects were also excluded because informed consent to participate in the study was not provided.
Weight and height of the participants were measured using a standard scale in light clothing. BMI was calculated as kg/m2 and categorized as underweight (<18), normal (18-24.9), overweight (25-29.9), obese (30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40), or morbid obese (>40). Mini Nutritional Assessment (MNA) was performed for screening of risk of malnutrition (=10 or =11).
Specifically designed questions were asked for each one of the following risk factors: sex, age, years of education (=5 year or =6 year), marital status (married, unmarried, widowed or divorced), living status (alone or with family), smoking (no/yes), alcohol (no/yes), family history of dementia (no/yes), number of drugs (=4 or =5). The diagnoses of hypertension, diabetes mellitus, stroke, myocardial ischemia, congestive heart failure were based on the diagnoses referred by the patient or care giver, a review of the clinical history and the use of specific medication.
All patients were evaluated through comprehensive geriatric assessment methods including the Mini-Mental State Examination (MMSE), the Clock Drawing Test (CDT), the Clinical Dementia Rating Scale (CDR), the Instrumental Activities of Daily Living Scale (IADL) and Hachinski Ischemic Scoring (13, 14). The patients were diagnosed using the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (15) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for Alzheimer's disease, the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN) (16) and DSM-IV criteria for vascular dementia, and Petersen criteria for MCI (17). In addition, all patients with dementia were evaluated using Magnetic Resonance Imaging.
Finally, the subjects were categorized into two groups according to having CD due to MCI, AD, and VaD or not.
Statistical analyses were performed using SPSS software version 15.0 (SPSS Inc, Chicago, II). The associations between categorical variables were examined with chi-square test. The effects of the variables on dementia were evaluated by calculating odds ratios in univariate analyses for all patients. Variables for which unadjusted p value was = 0.20 in univariate logistic regression analysis were identified as potential risk markers and included in the full multivariate model. The model was reduced using backward elimination method regarding likelihood ratio test results. A p value of less than 0.05 was accepted as statistically significant.
Results
1302 patients were included in the study. 905 (69.5%) subjects were not having CD whereas 397 (30.5%) patients with CD. The mean age was 77.71±6.86 years and 64.1% (n=864) of the sample was female. Of the patients with CD, 140 (10.4%) had MCI, 227 (16.9%) AD, and 30 (2.2%) VaD. The relationship between the social, demographic, and disease-based variables of the study population is presented in Table 1. In patients with CD, age, education, marital status, number of drugs, family history of dementia, BMI, MNA test score, and stroke were found to be significantly different from the subjects without CD.
Table 1.
Comparison of demographic, social status, physical condition, and medical history data according to cognitive status
| Cognitive decline (-)n(%) | Cognitive decline (+)n(%) | p* | ||
|---|---|---|---|---|
| Age | 905(69.5) | 397(30.9) | <0.001 | |
| Sex | female | 580 (64.1) | 284 (64.3) | 0.501 |
| male | 325 (35.9) | 158 (35.7) | ||
| Years of education | =5 year | 428 (47.5) | 245 (55.5) | 0.003 |
| =6 year | 473 (52.5) | 196 (44.5) | ||
| Marital status | married | 567 (63.7) | 247 (56.4) | 0.06 |
| Othera | 323 (36.3) | 191 (43.6) | ||
| Living status | alone | 182 (20.1) | 93 (21.0) | 0,371 |
| with family | 723 (79.9) | 349 (79.0) | ||
| Smoking | no | 787 (91.1) | 391 (92.0) | 0.831 |
| yes | 77 (8.9) | 34 (8.0) | ||
| Alcohol | no | 872 (96.3) | 428 (96.8) | 0.391 |
| yes | 33 (3.7) | 14 (3.2) | ||
| Family history of dementia | no | 328 (40.4) | 99 (23.6) | <0.001 |
| yes | 483 (59.6) | 321 (76.4) | ||
| Body mass index (kg/m2) | <18 | 4 (0.5) | 4 (1.0) | <0.001 |
| 18-24.9 | 107 (13.7) | 105 (26.7) | ||
| 25-29.9 | 308 (39.5) | 159 (40.5) | ||
| 30-40 | 336 (43.1) | 118 (30.0) | ||
| >40 | 24 (3.2) | 7 (1.8) | ||
| Mini nutritional assessment | =10 | 130 (29.9) | 64 (41.3) | 0.007 |
| =11 | 304 (70.1) | 91 (58.7) | ||
| Number of drugs | =4 | 211 (29.7) | 108 (28.3) | 0.043 |
| =5 | 416 (70.3) | 274 (71.7) | ||
| Hypertension | no | 258 (28.5) | 122 (27.6) | 0.39 |
| yes | 647 (71.5) | 320 (72.4) | ||
| Diabetes Mellitus | no | 698 (77.1) | 343 (77.6) | 0.452 |
| yes | 207 (22.9) | 99 (22.4) | ||
| Stroke | no | 835 (92.3) | 392 (88.7) | 0.021 |
| yes | 70 (7.7) | 50 (11.3) | ||
| Myocardial ischemia | no | 660 (72.9) | 328 (74.2) | 0.333 |
| yes | 245 (27.1) | 114 (25.8) | ||
| Congestive heart failure | no | 750 (93.6) | 390 (91.5) | 0.267 |
| yes | 51 (6.4) | 36 (8.5) |
chi-square test
other: unmarried, widowed or divorced.
Advanced age (OR=1.062; CI:1.043-1.081; p<0.001), unmarriedness (OR=1.357; CI:1.062-1.715; p=0.014), family history of dementia (OR=2.202; CI:1.689-2.871; p<0.001), polypharmacy (OR=1.302; CI:0.977-1.735; p=0.072), and stroke (OR=1.374; CI:0.916-2.060; p=0.124) were found to be potential risk factors for CD in the univariate model. However, overweight (OR=0.520; CI:0.349-0.774; p=0.001) and obese (OR=0.397; CI:0.265-0.593; p<0.001), high MNA score (OR=0.920; CI:0.859-0.985; p=0.017), and high education level (OR=0.746; CI:0.589-0.946; p=0.016) were found to be potential protective factors for CD. Factors including, gender, living status, smoking, alcohol, hypertension, diabetes, myocardial ischemia, and congestive heart failure were not reached statistical significance in univariate model.
Variables with p value less than 0.20 including age, years of education, marital status, family history of dementia, BMI, MNA, number of drugs, and stroke from the univariate model, were entered in a model for multiple regression analysis. Age (OR=1.054; CI:1.027-1.083; p<0.001) and family history of dementia (OR=1.662; CI:1.038-2.660; p=0.034) were found to be independent risk factors for CD. Overweight (OR=0.594; CI:0.370-0.952; p=0.03) and obese (OR=0.396; CI:0.242-0.649; p<0.001), and high education level (OR=0.640; CI:0.451-0.908; p=0.012) were found to be independent protective factors for CD. Marital status, MNA, number of drugs, and stroke didn't show statistical significance in multivariate model.
Discussion
In this study, it was demonstrated that overweight older persons have the lowest risk for CD as compared to those with normal weight.
Similar to other studies, the findings at the current study also imply that higher BMI values reduce the risk of CD (11, 12). On the other hand, there are several studies reporting high BMI is a potentially risk factor for CD. Whitmer et al. suggested that BMI at midlife is strongly predictive of both AD and VaD, independent of stroke, cardiovascular, and diabetes co morbidities (6). Gustafson found an association between overweight at age 70 and increased risk of AD in women, but not in men (18). Also, Hayden reported an association between obesity in late life and increased risk of AD in women (19). It is now known that the underlying neuropathological changes characterized with extracellular amyloid plaques and intracellular neurofibrillary tangles may be observed many years in advance of the onset of clinical symptoms of AD. As a result of AD, BMI may decrease and may emerge earlier than cognitive symptoms. In this respect, being overweight and obese in late life seem to be a protective factor for CD, however, it is more suitable to consider high BMI as a risk factor in midlife.
As taken together, these results imply new questions. Can weight loose taken to be a preclinical indicator of CD? Is it due to preclinical pathophysiologic changes or malnutrition? If that is a contributory factor, the focus on health prevention must change somewhat.
Although the ratio of women with CD was 64.3% in this study, female sex did not provide statistical significance for CD. Artero et al. reported that subjects with MCI were principally females (20). There are many studies reporting that the risk of AD is higher in women (21, 22, 23). However, regarding data from Rochester-Minnesota, France, and Odense studies, no significant and consistent variation occur with increasing age between gender groups (24, 25, 26). Few studies are available about the effect of gender on VaD. It was reported that the risk of VaD was slightly higher in men (25, 27). The protective effect of estrogens and the effect of survival difference in men are currently under investigation. For these reasons, gender difference is not considered as a distinctive risk factor for CD.
Low education level was found to be an independent risk factor for CD as reported in the other studies (p=0.012) (Table 2). Lower education level was reported as a risk factor for MCI and the onset of dementia, particularly for AD, whereas high education has a corresponding protective effect (20, 28, 29). The ‘cognitive reserve’ hypothesis was suggested to explain the low correlation between observed pathologic markers of dementia and clinical outcomes. According to this hypothesis, some individual features preserve cognitive function in case of brain pathology. Specifically, it assumes that on average, individuals with high education have greater brain reserve or compensational ability (30). This hypothesis may explain the delayed onset of clinically diagnosable dementia in individuals with high education (29, 31). MMSE and CDT were used to identify CD. It is known that the MMSE is influenced by education and lower levels of education result in lower scores, accordingly. Educated individuals can able to use their cognitive reserve to perform well on the MMSE despite having a decline from normal functioning (32, 33). Supplementing the standard MMSE with CDT may help to compensate this advantage.
Table 2.
Effects of variables on cognitive decline based on univariate and multivariate logistic regression analyses
| Unadjusted OR | 95%Cl | p value | Adjusted*OR | 95%Cl | p value | ||
|---|---|---|---|---|---|---|---|
| Age | 1.062 | 1.043-1.081 | <0.001 | 1.054 | 1.027-1.083 | <0.001 | |
| Sex | Male Female | 1.100 | 0.858-1.410 | 0.453 | |||
| Years of education | <5 year | ||||||
| >6 year | 0.746 | 0.589-0.946 | 0.016 | 0.64 | 0.451-0.908 | 0.012 | |
| Marital status | married | ||||||
| Other ∗∗ | 1.35 | 1.062-1.715 | 0.014 | 1.025 | 0.641-1.638 | 0.917 | |
| Living status | alonewith family | 0.884 | 0.663-1.178 | 0.400 | |||
| Smoking | noyes | 0.997 | 0.654-1.520 | 0.997 | |||
| Alcohol | noyes | 0.738 | 0.466-1.719 | 0.738 | |||
| Family history of dementia | no | ||||||
| yes | 2.202 | 1.689-2.871 | <0.001 | 1.662 | 1.038-2.660 | 0.034 | |
| Body mass index (kg/m2) | 18-24.9 | ||||||
| <18 | 0.284 | 0.032-2.492 | 0.256 | 0.312 | 0.031-3.165 | 0.325 | |
| 25-29.9 | 0.520 | 0.349-0.774 | 0.001 | 0.594 | 0.370-0.952 | 0.030 | |
| 30-40 | 0.397 | 0.265-0.593 | <0.001 | 0.396 | 0.242-0.649 | <0,001 | |
| >40 | 0.656 | 0.308-1.396 | 0.274 | 0.619 | 0.265-1.445 | 0.267 | |
| Mini nutritional assesment | <10 | ||||||
| >11 | 0.920 | 0.859-0.985 | 0.017 | 0.899 | 0.541-1.495 | 0.682 | |
| Number of drugs | <4 | ||||||
| >5 | 1.302 | 0.977-1.735 | 0.072 | 1.424 | 0.961-2.110 | 0.078 | |
| Hypertension | noyes | 1.027 | 0.790-1.336 | 0.840 | |||
| Diabetes | noyes | 1.017 | 0.769-1.346 | 0.905 | |||
| Stroke | no | ||||||
| yes | 1.374 | 0.916-2.060 | 0.124 | 1.321 | 0.731-2.388 | 0.357 | |
| Miyocardial ischemia | noyes | 0.969 | 0.742-1.265 | 0.815 | |||
| Conjestive heart failure | noyes | 1.314 | 0.856-2.028 | 0.210 |
Adjusted for age, years of education, marital status, family history of dementia, body mass index, mini nutritional assessment, number of drugs, and stroke.
Social status is important in old age. There are three longitudinal studies focusing on marital status. Their findings implied that the risk for dementia and Alzheimer's disease is lower among couples as compared with widowed, divorced, separated, or never married individuals (34, 35, 36).
Fratiglioni et al. showed that unmarried participants who lived alone and had no friends were at a higher risk of developing dementia (34). Helmer et al. found that initially non-demented elderly persons who were never married were at higher risk of dementia or AD than once married persons (35). The FINE study revealed that having a partner or living together with others is associated with a smaller CD (36). Three other studies focusing on living situation showed that men and women who lived alone were at an increased risk for CD comparing to those who lived with others (34, 36, 37). Several possible mechanisms could be argued to explain the protective effect of being married or living with someone against CD. One of them, the cognitive stimulation of each accompanier may protect the other's cognitive function from deterioration. Another proposed mechanism, the loss of a partner may result in changes of the lifestyle (alcohol, smoking, physical activity, dietary habits) or adverse health effects (stress and depression) then cognitive deteriorations occur accordingly. Findings of FINE and Fratiglioni et al.'s studies revealed that marital status may be a stronger predictor than living situation for CD and suggested that unmarriedness is associated with a higher risk for dementia than is living alone. In this study, being widowed, divorced or living alone were found to be risk factors for CD in univariate analysis, however, their significance were vanished in multivariate analysis (p=0.917) (Table 2). Living status did not reach significance, even in univariate analysis (p=0.400) (Table 2).
In the past decade, the vascular risk factors (hypertension, ischemic heart disease, diabetes, and smoking) and congestive heart failure were found to be associated with CD, including MCI, AD, and VaD (20,38,39,40) Results of the current study did not indicate to any relationship between these risk factors and CD; probably due to small sample size of patients with CD (n:397) or a cross sectional design of the study. Similarly, a recent cross-sectional study evaluated 175 patients and did not find any relationship (41). Mechanisms linking vascular risk factors to AD are still obscured. Several pathophysiological mechanisms are hypothesized to explain the association between these factors and AD.
It was founded that family history of dementia is an independent risk factor for CD (OR=1.662; CI:1.038-2.660; p=0.034). In the literature, family history of dementia is considered as a risk factor for AD (42, 43). However, prospective studies were not able to reveal an association between MCI, VaD and family history (44, 45). According to Kryscio et al., having a first-degree relative with dementia does not affect transition from normal to MCI. We think that family history may associate with increased risk of developing CD and this requires a larger longitudinal sample than was available for this analysis.
Stroke increases the risk of CD due to MCI, AD, and VaD (46, 47, 48). In a longitudinal follow-up study, a cohort of 1766 subjects, the hazards ratio for AD among those with a history of stroke was 1.6 (95% CI, 1.0-2.4) compared with those without stroke and the relation was strongest in the presence of known vascular risk factors (47). In a community cohort of 1301 subjects older than 75 years, relative risk for incident VaD related to history of stroke was 1.7 (95% CI, 1.1 to 2.6) (48). In our study, stroke ratio was significantly different among groups (p=0.021) (Table 1). However, such significance lost in the multivariate analysis (p=0.357) (Table 2). The small number of cases with VaD enrolled in the study may explain this.
The number of drugs were a risk factor for CD in univariate analysis which is lost its significance in multivariate analysis (p=0.078) (Table 2). Smoking and alcohol consumption did not found to have any relationship with CD (p=0.831, p=0.391, respectively) (Table 1)
There are some important limitations of the study. First, this is a cross sectional study, only providing information about associations but not causality between some of the variables presented. Secondly, the number of underweight persons included in the study was few. For this reason, it was not thought that the low ratio of CD in this group is significant. Furthermore, the number of patients with VaD was also few, which could alter the results by some way. Finally, it was considered that this study should extended to be a longitudinal study using the same population.
In summary, this study showed the risk of CD decreases in overweight and obese elderly. Such association in incidental CD is an original finding. The results indicate that the primary prevention should not only consider biological risk factors, but must also take anthropometric data into consideration in order to identify persons at high risk for CD. Losing weight in late life may be considered as a preclinical marker of the CD.
Financial disclosure: None of the authors had any financial interest or support for this paper.
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