Understanding the relationships between health and aging is essential for delaying morbidity and maximizing independence in aging populations as life expectancies increase. Loss of cognitive function is a feared age-associated condition and growing public health concern. Alzheimer’s disease (AD), the most common cause of dementia, has no curative therapies. Characterizing the relationships between risk factors, biomarkers, and AD progression is critical for the development of effective disease prediction, clinical intervention, and ultimately, disease prevention. The Emory Healthy Aging Study (EHAS) and the Emory Healthy Brain Study (EHBS), which is nested within EHAS, aim to further the understanding of healthy aging and the pathogenesis of age-related illnesses in well-characterized, community-based prospective cohorts and to identify biomarkers for the earliest manifestations of AD for the facilitation of preventative interventions. The EHAS is an innovative, longitudinal, web-based study enrolling English-speaking adults in the U.S. who agree to be contacted for future studies. Using validated instruments, the annual questionnaire enquires about demographics, socioeconomics, self-reported cognitive function, personal and family medical history, lifestyle, and psychosocial factors. Cognitive assessments are also obtained using an ambulatory device. Nested within EHAS, the EHBS is enrolling up to 2,500 EHAS participants, 50–75 years old, who do not have a diagnosis of AD, mild cognitive impairment, or any other memory disorder. EHBS in-person, biennial study visits, include neuropsychological testing, cardiovascular measures, retinal and brain imaging, biospecimen collection (blood, cerebrospinal fluid, gut microbiome), and other assessments. Since spring 2016, EHAS and EHBS have enrolled 12,500 and 863 participants with completed baseline assessments, respectively. Data and biospecimens from EHBS participants will support a broad range of AD biomarker discovery efforts, and follow-up of EHAS participants will enable assessment of self-reported cognitive trajectories and accumulation of incident cases of a variety of health conditions. The EHAS design supports the interval deployment of new study instruments and targeted sampling for ancillary studies. This project will increase our knowledge about healthy aging, improve our understanding of risk factors for cognitive impairment and dementias, support development of biomarkers, and facilitate studies of age-associated disorders including AD.