One in three seniors dies with Alzheimer's disease (AD) or another dementia - diseases that cost the nation $259 billion, to rise to $1.1 trillion by 2050 (Alzheimer's Association, 2017). Despite the vast personal and economic cost of these diseases, two major barriers stall efforts to discover key biological mechanisms that influence brain aging. First, the sheer cost of data collection means that most national initiatives have limited power to detect factors that affect brain aging. Even in datasets of N=1,000+ people (e.g., ADNI or the Parkinson's Progression Markers Initiative, PPMI) ? the power to discover modulators of brain aging is limited and may not generalize worldwide. Second, with the crisis of reproducibility, we do not always know if a finding will replicate; and if not, if this is due to true population heterogeneity or problems with methods. ENIGMA offers a coordinated global approach to solve these problems. ENIGMA's World Aging Center is a global brain aging study that builds on our vast and highly productive ENIGMA consortium - a global network of 340 institutions in 35 countries. ENIGMA published the largest-ever genetic studies of the brain (Hibar Nature 2015, 2017), and the largest neuroimaging studies of 5 major psychiatric disorders. ENIGMA's World Aging Center is a concerted global effort to pool all available data, methods, expertise and capital infrastructure to discover factors that affect brain aging. Our long-term goal is to identify personalized biological predictors of brain structural and functional decline and assess how they generalize globally. We have 4 aims:
Aim 1 : ENIGMA-Lifespan. Develop Lifespan Charts for Brain and Neural Tract Aging in 10,000+ people. We will create charts showing how MRI brain measures change throughout life in 10,144 people, aged 2-92. We will compute a composite brain aging score, `Brain Age', from available MRI, DTI, rsFMRI data, that measures how much the brain deviates from expected values, for a person's age and sex.
Aim 2 : ENIGMA-Epigenetics. Relate genome-wide methylation levels to brain metrics in 10,000+ people, to discover epigenetic markers of accelerated brain aging. We discovered 2 epigenetic loci promoting brain aging in pilot studies. We will compute a ?epigenetic clock? and test if it predicts brain metrics better than simple biological age.
Aim 3 : ENIGMA- Plasticity. Discover genomic loci that promote or mitigate brain tissue loss, in 31 worldwide cohorts with longitudinal MRI.
Aim 4 : ENIGMA-Parkinson's. Determine brain markers of PD across 10 cohorts worldwide (N=1,234 patients/864 controls), ranked by effect size. This will identify surrogate markers of PD for treatment trials.
These aims seek to analyze worldwide imaging, epigenetic, and clinical data with harmonized methods.
We aim to create new aging ?clocks? and reveal targetable risk factors and modifiers of brain aging in the genome, blood, and environment.
To address reproducibility and power issues in aging research, we launch ENIGMA's World Aging Center, a global brain aging study across 35 countries. Leveraging our ENIGMA network (340 institutions), we launch 4 coordinated projects to empower genetic, epigenetic, and environmental studies of brain aging: (1) Enigma- Lifespan- creates normative charts of brain aging metrics from MRI, diffusion imaging, and functional MRI in 10,000+ people worldwide; (2) ENIGMA-Epigenetics- relates genome-wide methylation to brain aging; (3) ENIGMA-Plasticity- seeking genetic loci affecting brain atrophy rates; and (4) ENIGMA-Parkinson's- to identify surrogate markers of PD for treatment trials. We will analyze worldwide imaging, epigenetic, and clinical data with harmonized methods, to create new aging ?clocks? and reveal targetable risk factors and modifiers of brain aging in the genome, blood, and environment.
