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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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

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


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

  • 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

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)

Critical P=0.0016

Ho et al., PNAS, 2010


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


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


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


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


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

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.


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

Stein Mol Psych

2011


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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