Ludwig Center Announces 2026 Pilot Grant Awardees
The Carol and Gene Ludwig Center for Research on Neurodegeneration is pleased to announce the recipients of its 2026 Pilot Grant Program: Drs. Peter St George-Hyslop, Amy Rumora, and Badri Vardarajan; and Drs. Christine Denny, Elisa E. Konofagou, and Raju Tomer. The two projects were selected for their innovative approaches to Alzheimer’s disease, cognitive resilience, and the biological changes that shape the aging brain.
“The biology of resilience is one of the most promising frontiers in Alzheimer’s disease research,” said Dr. Vilas Menon, co-director of the Carol and Gene Ludwig Center for Research on Neurodegeneration. “The 2026 pilot projects bring together complementary expertise and cutting-edge methods to investigate how genetic, cellular, neurovascular, and structural factors may protect the aging brain. This is precisely the kind of interdisciplinary work the Center seeks to catalyze.”
Drs. St George-Hyslop, Rumora, and Vardarajan will lead a project titled “Analysis of the Effects of a PLCG2 Resilience/Resistance Variant on Microglial Lipidomics and Bioenergetics in Human and Murine Models of AD and Aging.” Their study will investigate PLCG2 P522R, one of the strongest known genetic variants associated with protection against Alzheimer’s disease.
PLCG2 is highly enriched in microglia, the brain’s resident immune cells, and is involved in several core microglial functions, including activation, phagocytosis, cytoskeletal remodeling, and regulation of lipid metabolism. The investigators hypothesize that the P522R variant may protect against clinical Alzheimer’s disease and age-related cognitive decline by preventing microglial lipid dysmetabolism, preserving bioenergetic function, and reducing pro-inflammatory responses during aging and Alzheimer’s disease.
The project will integrate human cohort data, mouse models, lipidomics, bioenergetic profiling, and computational analyses to examine how PLCG2-mediated protection may operate across species and across the lifespan. By drawing on human datasets including ROSMAP, PARDoS, and WHICAP, and combining expertise in human genetics, microglial biology, lipid metabolism, and computational biology, the team aims to develop a systems-level understanding of how this protective variant may contribute to resilience.
Drs. Denny, Konofagou, and Tomer will lead a second project titled “Nanoscale Structural Signatures of Cognitive Resilience in Alzheimer’s Disease: A Multi-Scale Approach Using Expansion Microscopy, Focused Ultrasound, and Behavioral Stratification.” Their study will examine whether the architecture and functional integrity of synaptic and neurovascular networks help explain why some brains remain cognitively resilient despite Alzheimer’s-related pathology.
Using the APP/PS1 mouse model, the investigators will first identify cognitively resilient and vulnerable animals through advanced behavioral analyses and AI-assisted pose estimation. This behavior-first approach will allow the team to compare animals with different cognitive outcomes within the same genetic background, more closely reflecting the variability seen in human Alzheimer’s disease.
The investigators will then use whole-brain expansion microscopy with projected light-sheet imaging to generate nanoscale structural maps of synaptic and neurovascular architecture across wild-type, resilient, and cognitively impaired animals. In a second aim, they will use focused ultrasound-mediated neurovascular unit opening as a mechanistic tool to test whether neurovascular reserve contributes causally to resilience.
By combining behavioral neuroscience, advanced whole-brain imaging, and focused ultrasound, the project has the potential to generate an unprecedented structural atlas of resilience and vulnerability in Alzheimer’s disease. The work may also provide new insight into the relationship between neurovascular integrity, synaptic architecture, and cognitive outcomes.
Together, the 2026 pilot projects reflect the Ludwig Center’s commitment to supporting innovative, interdisciplinary research that looks not only at mechanisms of disease, but also at the biological pathways that may protect the aging brain. By advancing the study of resilience in Alzheimer’s disease, this year’s awardees are helping to lay the groundwork for future strategies to diagnose, monitor, prevent, and treat Alzheimer’s disease and related neurodegenerative disorders.