THE dangers of obesity are very well known. Being overweight is associated with an increased risk of coronary heart disease and stroke, the two leading causes of death in the Western world. Gout is more common in overweight people, with the risk of developing the condition increasing in parallel with body weight. Obese people are twice as likely to develop type 2 diabetes as those who are not overweight, and being overweight is also associated with several types of cancer. The list goes on...

Less well known is the effect of obesity on the brain. In the past few years, however, it has emerged that being overweight in middle age is linked to an increased risk of Alzheimer's Disease and other forms of dementia. Two new studies strengthen this association: the first, just published in the Annals of Neurology, shows that abdominal fat is linked to reduced brain volume in otherwise healthy middle-aged adults. The second, published last month in Proceedings of the National Academy of Sciences, shows that this reduction is associated with a common variant of an obesity-related gene.

Stephanie Debette of Boston University and her colleagues examined the association of various obesity indicators - including body mass index, waist circumference, waist-to-hip ratio and abdominal fat - with brain volume, as measured by structural magnetic resonance imaging. They recruited 733 participants for their study, all of whom were previously enrolled in the Framingham Heart Study, an ambitious longitudinal project started in 1948, whose aim is to identify the common factors contributing to cardiovascular disease by following the disease as it develops over long periods of time in large numbers of people. All of the earlier studies investigating the link between obesity and dementia have involved less than 300 participants, so this is the largest such study of its kind to date.

The researchers found that all of these obesity indicators were inversely associated with total brain volume - that is, the higher any indicator was, the smaller the brain volume - and that the association between abdominal fat and brain volume was the strongest of all. Waist-to-hip ratio was also found to be associated with increased temporal horn volume, independently of other obesity indicators. The temporal horn is a part of the ventricular system; its volume is known to increase with age, and in conditions such as Alzheimer's Disease, depression and schizophrenia. Enlargement of the temporal horn invariably involves a reduction in the volume of temporal lobe structures such as the hippocampus, and thus is closely associated with memory impairments. (Indeed, temporal horn volume could serve as a useful marker for Alzheimer's, in which the temporal lobe is one of the very first brain regions to be affected.)

In the second study, April Ho of the Laboratory of Neuro Imaging at the University of California, Los Angeles and her colleagues analysed data obtained from 206 healthy elderly participants as part of a large five-year research project called the Alzheimer's Disease Neuroimaging Initiative. The data were used to generate 3D maps of the participants' brains, and then to see if brain structure is related to one variant (or allele) of the fat mass and obesity associated (FTO) gene. This risk allele is strongly associated higher body-mass index - carriers have, on average, ~1.2kg higher weight and 1cm greater waist circumference. It is relatively common, being carried by some 46% of Western Europeans.

Ho's group found that the FTO risk allele also has a substantial effect on brain structure. Participants who carried at least one copy of the allele had marked reductions in the volume of various brain structures compared to average volumes in non-carriers and in the general population. Carriers of the allele had, on average, an 8% deficit in the volume of the frontal lobes and a 12% deficit in occipital lobe volume. A reduction in temporal lobe volume was observed in participants with a higher body-mass index, but not in carriers of the risk allele who have a body-mass index within the normal range. Those with higher body-mass index also showed volume deficits in all the other lobes of the brain, as well as in the brain stem and cerebellum (above).

Clearly, body-mass index and the FTO risk allele can affect brain structure independently of another, because significant differences in brain structure were observed in participants carrying the allele. FTO is known to highly expressed in the brain, and particularly in the cerebral cortex, but its function is still unclear, as is the mechanism by which a change in a single base pair in the gene can exert such a significant effect on brain structure. The reduced frontal lobe volume observed in carriers of the risk allele is interesting, as it has previously been associated with impairments of so-called executive functions, as well as in several types of memory, all of which are also impaired in Alzheimer's and other forms of dementia.



How might being overweight or obese lead to a reduction in brain volume? Inflammation could mediate the effects of obesity on the brain. Adipose (fat) tissue is known to produce chemicals called cytokines, which may contribute to neurodegeneration. It contains immune system cells called macrophages and monocytes, too, which are also implicated in Alzheimer's.

Whatever the mechanism, the recent findings have important health implications. Obesity is a major public health concern - there are some 300 million obese, and more than 1 billion overweight, people worldwide. These studies, and others that came before them, suggest that maintaining normal body weight throughout adulthood - and especially middle age - could minimize the risk, or even prevent, the onset of dementia in later life. They also reiterate the emerging view that changing one's lifestyle - and particularly taking regular physical excercise - is probably the most effective way of reducing the risk of dementia in later life.

Debette, S., et. al. (2010). Visceral fat is associated with lower brain volume in healthy middle-aged adults Ann. Neurol. DOI: 10.1002/ana.22062

Ho, A., et. al. (2010). A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc. Nat. Acad. Sci. 107: 8404-8409. [PDF]

Rosengren, A., et. al. (2005). Body Mass Index, Other Cardiovascular Risk Factors, and Hospitalization for Dementia. Arch. Intern. Med. 165: 321-326 [PDF]

Gorospe E.C. & Dave, J. K. (2007). The risk of dementia with increased body mass index. Age Ageing 36: 23-29. [PDF]