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

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ADNI (N=587,critical P-value: 0.025)

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Adni n 587 critical p value 0 025

Higher BMI (body mass index) is linked to greater brain atrophyin 700 MCI and AD patients, and in healthy elderly

(N=113, critical P-value: 0.011)

ADNI (N=587,critical P-value: 0.025)

Ho, Raji et al., Neurobiology of Aging, 2010


Higher bmi associated with similar pattern of atrophy in the subgroup of 476 mci subjects

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


Adni n 587 critical p value 0 025

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

AIM 1

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)


Obesity associated gene fto relates to brain structure

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)


Adni n 587 critical p value 0 025

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

Higher BMI associated with widespread pattern of atrophy

Ho et al., PNAS, 2010

Critical P=0.0202


White matter burden does not explain effect of fto risk allele on brain atrophy n 169

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 you in a different way

Depending on your FTO genotype, BMI seems to affect youin a different way

1 or 2 risk alleles

N=128, critical P=0.016

2 risk alleles

N=33; critical P=0.0022

1 risk allele

N=95; critical P= 0.0113

*Does not pass FDR

at 5% in non-carriers (N=78)

Ho et al., PNAS 2010


Adni n 587 critical p value 0 025

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

RajagopalanNeuroReport2011


Adni n 587 critical p value 0 025

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)

RajagopalanNeuroReport2011


Higher physical activity correlated with greater brain volume

What else can be done about atrophy?

Higher physical activity correlated with greater brain volume

Ho and Raji et al., Human Brain Mapping, 2010

Critical P=0.0003


Higher educational level is correlated with greater temporal lobe volume

What can be done about atrophy?

Higher educational level is correlated with greater temporal lobe volume

Ho and Raji et al., Human Brain Mapping, 2010

Critical P=0.0021


Genome wide association study

Genome-wide association study

Where in the genome is a common variant (carried by >1% of the population)

associated with a brain measure?

One SNP

600,000 SNPs

P-value

Caudate Volume Change

Position along genome

A/A

C/C

A/C

Genotype

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


Adni n 587 critical p value 0 025

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

Stein Mol Psych

2011


Adni n 587 critical p value 0 025

Replication through collaboration

http://enigma.loni.ucla.edu

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


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