McCance Seminar Series: Tracy Young Pearse, PhD

Why It Matters

The iPSC‑based platform bridges genetic risk to cellular phenotype, accelerating precision‑medicine approaches for Alzheimer’s drug discovery and offering a collaborative resource to test candidate interventions across diverse genetic backgrounds.

Key Takeaways

• iPSC models capture individual genetic risk and resilience for Alzheimer’s.
• Heterogeneity in plaques, tangles, and cognition observed in ROSMAP cohort.
• ABAB7 and NPP5D variants influence microglial activation and synaptic vulnerability.
• Multi‑omic profiling links cell‑type specific signatures to brain tissue concordance.
• Collaborative iPSC platform enables functional testing of Alzheimer’s genetic variants.

Summary

Dr. Tracy Young‑Pearse presented a seminar on leveraging induced pluripotent stem cell (iPSC) technology to dissect how Alzheimer’s disease (AD)‑associated genetic variation influences cellular function, with a focus on microglial biology and the blood‑brain barrier. By deriving iPSC lines from over 120 participants in the ROSMAP and Memory and Aging Project cohorts—individuals with detailed longitudinal cognitive data, neuropathology, and multi‑omic profiles—her lab creates living human brain cell models that retain each donor’s unique genetic risk and resilience factors.

The talk emphasized the profound heterogeneity observed both in clinical trajectories and in neuropathological burden, noting that many cognitively normal individuals harbor substantial amyloid plaques and tangles. Using genome‑wide association data (70+ AD loci) and rare mutations, the team differentiates iPSCs into neurons, astrocytes, and microglia, then applies transcriptomic, proteomic, and secretome analyses. Specific findings highlighted include how loss‑of‑function variants in ABCA7 and NPP5D modulate microglial activation, lipid metabolism, and downstream synaptic vulnerability, illustrating distinct molecular “roads” that converge on classic AD pathology.

Unpublished analyses demonstrated strong concordance between cell‑type specific omic signatures in vitro and corresponding measurements from the donors’ post‑mortem brain tissue, validating the physiological relevance of the models. Computational biologists in the lab performed QTL mapping across cell types and identified cell‑type‑specific expression quantitative trait loci, providing a framework for probing any gene of interest within the existing dataset.

These efforts create a scalable, collaborative platform for functional genomics in AD, enabling precise interrogation of genetic variants, rapid testing of small‑molecule modulators, and the potential to uncover novel therapeutic targets tailored to individual genetic backgrounds.

Original Description

Tracy Young-Pearse, PhD, presents: "Dissecting the functional consequences of Alzheimer’s disease-associated genetic variation in microglia" as part of the McCance Center for Brain Health Seminar Series. https://www.massgeneral.org/neurology/mccance-center