Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60–80% of cases 
. At present, about 33.9 million people worldwide have AD, and the prevalence is anticipated to triple over the next 40 years owing to demographic changes and longer life expectancies 
. Available drugs for dementia and AD have small effect sizes and do not clearly alter disease progression 
As delaying symptom onset by as little as 1 year could potentially lower AD prevalence by more than 9 million cases over the next 40 years 
, there has been growing interest in identification of preventive measures. Observational studies have assessed a wide range of potentially modifiable risk factors, in particular cardiovascular risk factors. While for diabetes the association with AD seems clear 
, the association for most other cardiovascular risk factors, including obesity, remains largely inconsistent across studies. For obesity, most studies show an increased risk 
, but some show an inverse risk 
, some show nonlinear associations 
, and some show no association 
. Explanations for the conflicting data include reversed causation, residual confounding, potential survival bias, and decreased validity of body mass index (BMI) as a measure of obesity in the elderly 
. In general, measures of central obesity, particularly waist to hip ratio (WHR), seem to be better predictors of cardiovascular outcomes compared with BMI 
, and central obesity in middle age is related to a higher risk of dementia.
Recent studies have demonstrated that polymorphisms in the Fat and Obesity-Associated (FTO) gene have strong and robust effects on obesity and obesity-related traits (such as body mass index (BMI), waist circumference, waist to hip ratio, bicondilar upper arm width and upper arm circumference) 
is located on chromosome 16q12.2, has nine known splice variants and is highly expressed in the brain. Although this gene has nine exons, all reported polymorphisms are part of one LD block spanning 47 kb across intron 1, exon 2 and part of intron 2 ().
Genomic organization of FTO and its neighboring genes (not drawn to scale).
The same polymorphisms have also independent strong effects on insulin resistance/Type 2 Diabetes, which is – as described above- a strong risk factor for AD 
, metabolic syndrome 
, obesity-related dyslipidemia 
, and changes in blood pressure 
. In addition, several studies reported associations of genetic variation in FTO
with traits that are common endophenotypes of dementia. In the Alzheimer's Disease Neuroimaging Initiative (ADNI), the FTO
polymorphism most commonly associated with obesity and in Caucasians (rs9939609 (Intron 1)) was associated with reductions in frontal and occipital lobe volumes 
. In a Swedish dataset involving 355 old men at the age of 82 years from the Uppsala Longitudinal Study of Adult Men (ULSAM), rs9939609 was associated with impairment in verbal fluency 
. In the only study to date that assessed the effect of genetic variation in FTO
on AD risk, a longitudinal cohort study of the Kungsholmen project that involved 1,003 Caucasians followed for 9 years, the minor allele of rs9939609 was associated with a 1.6-fold risk of developing AD 
. The advantage of relating genetic variation with a phenotype of interest is that it overcomes the issues of reverse causation and residual confounding 
The goal of the present study was to further clarify whether genetic variation in FTO, that is similar to or in linkage disequilibrium (LD) with the SNPs previously reported to be associated with obesity-related measures or AD endophenotypes is associated with AD. We explored this question by genetic association analyses of two independent case-control datasets that are derived from different ethnic groups and have sufficient power to detect modest effect sizes. In addition, we peformed a meta-analysis that also included the publicly available ADNI dataset, and conducted microarray gene expression analyses of two independent samples.