1. Higher BMI (body mass index) is linked to greater brain atrophy in 700 MCI and AD patients, and in healthy elderly ADNI (N=587,critical P-value: 0.025) (N=113, critical P-value: 0.011) Ho, Raji et al., Neurobiology of Aging, 2010

2. CHS, N=77; critical P-value: 0.009 ADNI N=400, critical P-value: 0.019 Ho and Raji et al., Neurobiology of Aging, 2010

3. Critical P-value: 0.012 Ho and Raji et al., Neurobiology of Aging, 2010

4. AIM 1

5. Background: – FTO (fat mass and obesity-associated) gene highly expressed in the brain Frayling et al., 2007 – Carried by 46% of Western Europeans – BMI is highly genetically influenced (genetic factors explaining 50-90% of the variance in BMI) – Associated with a ~1.2 kg weight gain and ~1 cm waist circumference increase – carriers eat, on average, 200 more calories a day – Carriers (2 copies of the variant) were 67% more likely to be obese than non-carriers Frayling et al., 2007 – Used proxy (tagging SNP) that has 98.8% accuracy in predicting risk allele PNAS paper (Ho 2010): this very common obesity-associated risk allele is associated with lower brain volume in similar areas affected by obesity Study Design: Cross-sectional study using TBM in 206 ADNI controls (healthy elderly)

6. Carriers of obesity risk allele, in FTO, have greater atrophy in frontal and occipital lobes (206 ADNI controls) Critical P=0.00131 Ho et al., PNAS, 2010

7. Higher BMI associated with widespread pattern of atrophy Critical P=0.0202 Ho et al., PNAS, 2010

8. White matter burden does not explain effect of FTO risk allele on brain atrophy (N=169) Critical P=0.0016 Ho et al., PNAS, 2010

9. Depending on your FTO genotype, BMI seems to affect you in a different way 2 risk alleles 1 risk allele 1 or 2 risk alleles N=33; critical P=0.0022 N=95; critical P= 0.0113 N=128, critical P=0.016 *Does not pass FDR at 5% in non-carriers (N=78) Ho et al., PNAS 2010

10. What can be done about this? We found that the level of atrophy was linked with high levels of homocysteine in the blood (N=732, all ADNI subjects) – vitamin B/folate supplements may reduce this Rajagopalan NeuroReport 2011

11. Homocysteine levels in the blood explain a substantial proportion of brain atrophy (N=356 MCI subjects only) – dietary folate supplements may reduce this (testable in a trial) Rajagopalan NeuroReport 2011

12. What else can be done about atrophy? Critical P=0.0003 Ho and Raji et al., Human Brain Mapping, 2010

13. Critical P=0.0021 Ho and Raji et al., Human Brain Mapping, 2010 What can be done about atrophy?

14. Genome-wide association study Where in the genome is a common variant (carried by >1% of the population) associated with a brain measure? Genotype A/AA/CC/C Caudate Volume Change One SNP600,000 SNPs Position along genome P-value GWAS = Finding common variants which explain the heritability of a trait.

15. Discovered Genes for Caudate Volume - ADNI top hit (dopamine pathway gene) was replicated in young adults Stein Mol Psych 2011

16. http://enigma.loni.ucla.edu Replication through collaboration 83 members from 9 countries, GWAS meta-analysis in 19 cohorts (N>7,000)