Brain structure undergoes changes throughout life as part of the normal healthy aging process, yet some genetic factors embedded in our DNA are believed to alter and potentially accelerate the aging process within the brain. While numerous neuroimaging studies have aimed to map the genetics of dementia, differences in populations and approaches confounded with the small effect sizes attributable to any single genetic variant leads to inconsistencies in findings and limited resources to investigate the truth. Dozens of neuroimaging genetic studies have been collected around the world to help better understand the link. However, the independent nature by which the studies often operate may be limiting scientific advance. Instead of collecting new data to answer the same questions, we harmonize brain mapping efforts across existing studies and pool information to not only study differences between the healthy and demented brain, but also examine normal healthy aging trends, and determine the first signs of deviation, and map out the neurobiological effect of genes that confer risk for dementia. In our effort, we aim to pinpoint mechanistic trajectories and brain circuits by which the widely studied ApoE4 genetic haplotype affects brain throughout life. Despite being identified as a genetic risk for Alzheimer's disease over 20 years ago, the effects on the brain in populations around the world are remarkably inconsistent. With novel brain mapping techniques across tens of thousands of individuals across the lifespan, we will perform the most well powered brain mapping initiative and build necessary tools to invite other researchers from around the world to add confidence to the findings. We will also determine ? with unprecedented power -- how the aggregate risk for AD promotes accelerated brain degeneration with novel expedited longitudinal linear mixed modeling techniques for large scale epidemiological genetic studies with repeat data. Our proposal brings together contributions from multidisciplinary collaborators with world renowned expertise in neurodegeneration, brain mapping, big data, artificial intelligence, epidemiology, genomics and epigenomes, statistical genetics, and molecular and biological psychiatry. Our technical expertise will provide resources for visualizing genetic results at the finest resolution and provide tools for researchers to use our harmonized analyses to structure their own aging hypotheses in populations of men and women around the world, and even target sex-specific hypotheses in aging. As new brain imaging and genetic data is becoming rapidly available, we provide the tools to harmonize the data into this workflow for years to come. Driven by the data sharing and reuse of this proposal, we provide a portal for researchers of today and tomorrow to access findings from all the studies incorporated in this proposal and add to the collective repository of effects. We hope our careful harmonization of data, along with novel mathematics, tools, and selection of targeted hypotheses will guide future collaborative studies for continuous reuse.
/RELEVANCE Brain aging is a global health concern and a major focus of dozens of large scale research initiatives around the world. Here, we propose a paradigm to use advanced brain imaging techniques in a harmonized fashion across numerous existing datasets, and to map the underlying genetic influences driving neurodegeneration across tens of thousands of individuals. We will provide advanced brain image processing, mathematical tools, and a portal for researchers to access and add to findings.