The Adult Changes in Thought (ACT) U19 Program will expand, modernize, and improve ACT's prospective cohort study to achieve advances in scientific understanding of older adults in general and dementia and Alzheimer's disease in particular. ACT is set in a healthcare delivery system. The study team identifies incident cases of dementia and Alzheimer's disease and follows consenting participants to autopsy. The Program will transform the current ACT U01 to a U19, which envisions complex multi-component programs that will have a powerful influence on the field. The Program's overarching goal is to identify risk factors across the life course that provide potential intervention targets for preserving cognition and preventing Alzheimer's disease and related dementias (ADRD). The Overall Specific Aims are: Aim 1. Expand ACT cohort enrollment and modernize and improve follow-up with emphasis on increasing racial/ethnic diversity and deep phenotyping of life course risk factors, cognitive and physical functioning, and outcomes including neuroimaging and neuropathology based ADRD outcomes. The Cores will expand cohort enrollment from 2,000 to 3,000. The study will invest in six Cores: A, Administrative; B, Clinical; C, Life Course; D, Neuropathology; E, Neuroimaging; F, Data and Analysis. These Cores will work together to further enhance the value of ACT's resources, enabling the ACT study to continue to be the foundation for an extraordinary array of science. To date, ACT has achieved a completeness of follow-up index of 94.5% and has observed 56,140 person-years of follow-up. ACT has identified >1,300 incident dementia cases and >1,000 incident Alzheimer's cases. The study has completed >850 autopsies and will surpass 1,100 autopsies this cycle. Additionally, 1,077 ACT participants had one MRI scan, and 540 have had ≥2, with funding in place for hundreds more. Aim 2. Support key Projects studying the spectrum of healthy functioning to ADRD in older adults. The three Projects center around 24-hour cycle physical activity, sedentary behavior, and sleep patterns in old age (Project 1), the implications of cognitively defined Alzheimer's disease subgroups (Project 2), and mechanisms underlying neural protection and toxicity of strong anticholinergic drugs and antihypertensive drugs (Project 3). Aim 3. Expand and improve ACT's dissemination of exceptional resources to the research community guided by NIA's adopted FAIR (Findable, Accessible, Interoperable, and Reproducible) principles. ACT has proven to be an exceptional resource to the research community, providing data and specimens to research colleagues locally, across the country, and around the world, and provides mentorship to junior investigators. We will continue to enhance our data sharing capabilities in this U19 Program.

This proposal seeks to improve understanding of aging, brain aging and dementia specifically by expanding, modernizing and improving a longstanding cohort study of older adults enrolled from a healthcare delivery system with extensive records from clinical care. The Adult Changes in Thought (ACT) U19 Research Program has identified incident cases of dementia (>1,300 to date) and Alzheimer's disease (>1,000 to date) and follows consenting participants to autopsy (>850 to date). The U19 Program will provide valuable data on extremely well characterized individuals and aims to identify targets for prevention and treatment of Alzheimer's disease and other age-related disorders and facilitate greater collaborative research by expanding and improving dissemination of our exceptional resources.