Advancing a systems-level understanding of neurodegeneration: the BrightFocus Alzheimer's disease research portfolio.

Alzheimer's disease research is entering a period of rapid acceleration. After decades focused on identifying individual disease-associated proteins and pathways, the field is moving toward a deeper understanding of how these mechanisms interact to influence cellular function, biological systems, and ultimately behavior and cognition. The emphasis is moving from isolated molecular targets to coordinated biological systems. Underlying pathological mechanisms point toward the breakdown of core cellular maintenance systems, including proteostasis, metabolism, and immune regulation. This dysfunction propagates from organelles to cells, from cells to neural circuits, and, ultimately, to cognition and behavior. Moving beyond single-target approaches will depend on understanding these upstream drivers, how they interact, and how sex, genetic background, and accumulated stressors shape when and how these systems fail. Underlying pathological mechanisms point toward the breakdown of core cellular maintenance systems, including proteostasis, metabolism, and immune regulation. This dysfunction propagates from organelles to cells, from cells to neural circuits, and ultimately to cognition and behavior. The BrightFocus Alzheimer's Disease Research (ADR) program [1] has long operated within this broad framework. Rather than focusing narrowly on single disease targets, the portfolio takes a 360° approach and prioritizes innovative research that reveals how fundamental cellular processes interact across cell types and biological systems to drive neurodegeneration and resilience. This includes supporting early-career investigators and researchers entering the field from other disciplines to advance current hypotheses and define where the field is going next.