This study found that elevated BMI is associated with reduced brain volumes, suggesting greater global brain atrophy in middle-aged adults even after adjusting for age. Episodic learning, working memory, and processing speed abilities were not associated with BMI in this sample indicating that the possible effect on cerebral atrophy had not influenced cognition in participants with a high BMI. Episodic learning was related to diastolic BP, which indicates that certain cardiovascular risk factors may be associated with cognition. However, this finding was isolated to only one of our three categories of cognition. Longitudinal studies are needed to assess future cognitive consequences associated with cardiovascular risk factors.
Our finding that BMI affects brain volume at a relatively young age extends prior research on the harmful effects of obesity on the brain. We found a 2.4% difference in brain parenchyma volume for participants classified by the WHO as obese (n = 21 people; average BMI= 33.3 kg/m2
) compared to participants at a normal, healthy weight (n = 51 people; average BMI = 22.6 kg/m2
). Although the magnitude of this difference is not large in this cross-sectional sample, when we consider these results in the context of the younger age of our sample (54.2 years), it follows that obesity in middle age may render an individual more vulnerable to brain atrophy over subsequent years, and thus more vulnerable to cognitive decline or dementia. The results of this study are consistent with others showing that life choices (i.e., proper diet, physical activity) may be neuroprotective and, therefore, potentially reduce the rate of brain atrophy and concomitant cognitive decline [27
]. A longitudinal study of obese people at middle age is needed to test these hypotheses.
It is unclear through what mechanisms obesity affects brain volume. Central obesity is associated with risk factors composing the metabolic syndrome, including high triglyceride levels, low HDL cholesterol levels, hypertension, insulin resistance, and prothrombotic and proinflammatory states. Prior studies indicate that some of these risk factors such as mid-life elevations in blood pressure, total cholesterol, and inflammatory markers, are risk factors for late-life dementia[13
]. In the present study, neither BP nor non-fasting total cholesterol was associated with current NBV (though systolic BP did show a trend). These vascular risk factors may affect chronic cerebral perfusion and β-amyloid generation, thus influencing neuronal degeneration. Leptin, a peptide related to obesity, also affects β-amyloid regulation [32
]. Further studies are needed to determine the mechanism by which BMI affects brain atrophy in middle-aged adults, and whether this may have future deleterious consequences on brain structure or function.
Brain tissue is strongly dependent upon oxygen for survival and is thus vulnerable to hypoxic and ischemic conditions. Hypoxia is an inherent consequence of many of the conditions caused or exacerbated by obesity. Obstructive sleep apnea[4
], CHD [33
], asthma [34
], and low cardiovascular fitness[21
] may lead to hypoxia which, in chronic situations, may lead to cognitive decline and neuronal death[35
]. Hypoxia is often a consequence of hypoperfusion, which is strongly associated with endothelial dysfunction common to individuals with hypertension, atherosclerosis, and CHD. Endothelial dysfunction, as a result of oxidative stress, may induce neuronal damage and initiate neurodegenerative change[17
Prevention or postponement of the onset of dementia has the potential to drastically impact the prevalence of dementia. The prevalence of AD in the United States alone is projected to quadruple in the next 50 years, and if disease onset could be delayed by only one year, it would result in 800,000 fewer cases[36
]. It has been shown that a person's weight is a reflection of their habitual physical activity[4
]. Given the rapid increase in obesity in the United States, targeting weight management may significantly impact the prevalence of dementia. High dietary fat intake has been shown to increase the risk of dementia [37
]. Physical fitness significantly improves cognitive function in older adults[21
] and exercise increases the production of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor I (IGF-I). BDNF and IGF-I are neurotrophic hormones that are important for neurogenesis, which may protect against neurodegeneration seen with aging[38
]. In older adults the rate of change in brain volume may be diminished in persons with better cardiovascular fitness[39
There were some limitations of this study. First, the range of BMI was truncated because of the small-bore radius (55 cm) inherent to the MRI scanner. Therefore, participants in this study could not exceed 260 pounds, which did not permit an analysis of the effects of extreme obesity. Next, insulin-dependent diabetic participants were excluded from this study because diabetes has been shown to be a risk factor for dementia [18
] and therefore could be an important confounder in the analysis. The incidence of diabetes in our study population was less than 1%, which was not enough to determine its affect on global brain volume. Next, the design of this study was cross-sectional which only allowed for inferences between participants over a single time point. A longitudinal study is needed to clarify if the reduced brain volume associated with elevated BMI is representative of a progressive brain atrophy and concomitant cognitive decline. Additionally, non-fasting, instead of the more accurate fasting blood cholesterol values were used as potential predictors of NBV. Furthermore, the BMI measurement itself is only an estimate of obesity; it does not accurately distinguish fat mass from lean mass. The highest risk for adverse consequences related to overweight individuals are best indicated by excess amounts of adipose tissue, especially that within the intra-abdominal region. Waist circumference and skinfold thickness measurements in conjunction with BMI would have provided a more precise measure of the amount and location of this excess body fat. Finally, this study population was self-selected from a group of highly educated, motivated volunteers; these findings may not be representative of the general population. However, these findings are important in understanding how to potentially target preventive therapies for at-risk individuals.