PROJECT SUMMARY Older individuals represent 15% of the United States population, and this is expected to exceed 20% by 2050. It is therefore critical that we improve our understanding of the physiology of healthy brain aging and the mechanisms that may lead to dysfunction in older people. It is well accepted that the brain is functionally organized into multiple interacting networks. The reliable and reproducible identification of brain functional networks crucially depends on the use of reference functional atlases. Extensive literature has demonstrated that the spatial and functional organization of the brain connectome shows age-related alterations in later life. Yet, there is currently no reference brain functional atlas derived from older adults, and this may undermine the validity and reliability of neuroimaging research in late adulthood. Using pilot data for this application, we show that an age-appropriate brain functional atlas will improve the characterization of the brain functional connectome and its links to cognition in late adulthood. In this context, the aim of this application is to construct and validate the first reference brain functional atlas in healthy adults above the age of 55 years. To achieve this, we will use resting-state functional magnetic resonance imaging (rs-fMRI) from three large, independent and publicly available neuroimaging datasets. Our first aim (Aim 1) is to generate a reference atlas, called “Atlas55+”, using the largest rs-fMRI dataset currently available from the Cambridge Centre for Ageing and Neuroscience (CamCAN) repository (n=326). We will demonstrate the replicability of Atlas55+ in two independent large samples of older healthy participants derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=200) and the Southwest University Adult Lifespan Dataset (n=191) (Aim 2). Because women, on average, have a longer life expectancy than men, we will test whether older women show brain network differences compared to older men. In the event of significant sex differences, we will create the first sex-specific brain functional atlases in older adults (Aim 3). Fourth, we will demonstrate the superiority of network connectivity features derived from Atlas55+ compared to an atlas based on data from younger people in predicting a greater amount of the variance in fluid intelligence in healthy older adults and in Mini Mental Status Examination score in patients with Alzheimer's disease or mild cognitive impairment (Aim 4). The successful completion of this project will provide the first reliable brain functional atlas for adults over the age of 55 years which will be made freely available to other researchers. By mapping the brain functional connectome underlying late adulthood, this work has the potential to elucidate how dysfunction of the brain networks contributes to neurodegenerative conditions.

PROJECT NARRATIVE Understanding changes in the brain architecture relating to aging is a major public health challenge as life expectancy continues to increase. This project aims to construct and validate the first ever functional reference brain atlas for adults above the age of 55 years (Atlas55+) and to demonstrate its value in predicting cognitive function in healthy older adults and in individuals with Alzheimer's disease or mild cognitive impairment.