SUMMARY The Adult Changes in Thought (ACT) Neuropathology (NP) Core (Core D) has been a valuable and frequently utilized resource for the ACT cohort and supports the ACT Repository where the most generous gift to science – a person’s brain – is used to maximize impact on local and national science of Alzheimer’s disease and related dementias (ADRD). The NP Core has instituted rapid protocols designed for cutting edge molecular cell profiling and has markedly extended sampling strategies to better capture regional changes that underlie the heterogeneity of Alzheimer’s disease and related dementias. The NP Core has fostered development of innovative, highly quantitative approaches to assess the neuropathology of ADRD, building on this important tradition by integrating imaging technologies and analytical approaches to target and quantify gross and microscopic pathology. We perform post-mortem MRI on every brain, generate 3D virtual brain reconstructions leveraging unique brain sectioning techniques in the NP Core, scan slides of prospective and archival ACT samples for traditional quantitative image analysis supplemented with deep learning approaches to maximize information yield, and leverage multiplexed solution-phase assays from fixed-tissue protein extracts to compare cytoarchitectural and biochemical pathologic changes in ADRD. All of these innovations are designed to enable us to deeply characterize the structural substrate for ADRD heterogeneity, mechanisms of resilience and resistance, and the biological basis of cognitive subtypes and functional variations in brain aging and dementia in support of each of the ACT Cores. We combine this comprehensive analysis of human brains with a leptomeningeal cell resource and neuropathological characterization for mechanistic explorations of AD pathophysiology (Project 3) and promote existing collaborations focused on characterizing cell type vulnerabilities in all stages of AD to inform mechanistic, diagnostic, and therapeutic research. The NP Core interacts with and supports every other ACT U19 Research Program Core and Project through state-of-the-art diagnostics and has expanded dissection and assessment protocols specifically tailored to support Project 2. Thus, our Aims reflect our commitment to integrate traditional diagnostic excellence and extensive tissue and data sharing with radiographically informed extensive sampling and a battery of highly quantitative, molecularly specific tissue and in silico approaches to precisely measure ADRD neuropathology. Our specific Aims are to (1) build a highly accessible repository of brain tissue and fluids, (2) provide diagnostic expertise according to the latest guidelines, (3) develop innovative approaches, and (4) promote durable ADRD research through support of ACT Cores and Projects. All of our research activities are focused on enhancing the research value of tissue and body fluid donations from cognitively healthy ACT participants and those along th...