Higher BMI (body mass index) is linked to greater brain atrophyin 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

Higher BMI associated with similar pattern of atrophy in the subgroup of 476 MCI subjects

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

Surprisingly, this is still true in AD:Higher BMI is linked with more severe (~2%) brain

volume reduction 188 AD patients

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

Implications

• First study to show that higher BMI is correlated with regional profiles of brain atrophy in both healthy and cognitively impaired persons

• Results were reproduced in two independent samples• Strength of the BMI-brain atrophy relationship in

healthy control, MCI, and AD emphasizes the need to consider obesity as risk modifying for cognitive impairment

• Controlling body fat content even in late life may reduce risk for dementia (interventional studies are needed)

AIM 1

Obesity-associated gene (FTO) relates to brain structure

• 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)

Carriers of obesity risk allele, in FTO, have greater atrophyin frontal and occipital lobes (206 ADNI controls)

Critical P=0.00131 Ho et al., PNAS, 2010

Higher BMI associated with widespread pattern of atrophy

Critical P=0.0202 Ho et al., PNAS, 2010

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

Depending on your FTO genotype, BMI seems to affect youin 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

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

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

Higher physical activity correlated with greater brain volume

What else can be done about atrophy?

Critical P=0.0003 Ho and Raji et al., Human Brain Mapping, 2010

Higher educational level is correlated with greater temporal lobe volume

Critical P=0.0021 Ho and Raji et al., Human Brain Mapping, 2010

What can be done about atrophy?

Genome-wide association studyWhere in the genome is a common variant (carried by >1% of the population)

associated with a brain measure?

Genotype

A/A A/C C/C

Cau

date

Vol

ume

Cha

nge

One SNP 600,000 SNPs

Position along genome

P-value

GWAS = Finding common variants which explain the heritability of a trait.

Discovered Genes for Caudate Volume - ADNI top hit (dopamine pathway gene) was replicated in young adults

Stein Mol Psych2011

http://enigma.loni.ucla.edu

Replication through collaboration

83 members from 9 countries, GWAS meta-analysis in 19 cohorts (N>7,000)