Alzheimer's disease accounts for 60–80% of dementia cases, but its biology extends well beyond amyloid plaques and tau tangles, involving neuronal hyperexcitability, glial reactivity, vascular breakdown, and more than 80 associated genetic risk loci.

In this webinar, Dr. Kellianne Alexander of the Young Pierce Lab will share findings from ROSMAP, a cohort of over 4,000 participants whose brains are donated at death. The lab has generated 100+ iPSC lines from ROSMAP donors — spanning AD, resilient, and low-pathology groups — differentiated into neurons, astrocytes, microglia, pericytes, and endothelial cells to study how human genetics shape disease.

Using live-cell and multi-electrode array assays, the lab found that AD neurons show elevated synaptic vesicle release and network bursting that correlate with donor amyloid burden, a pattern also seen in familial AD models carrying APP and presenilin mutations. Beyond neurons, amyloid beta drives cell type–specific effects across the neurovascular unit, including MMP activation in endothelial cells and shared "matrisome" dysregulation linked to AD pathology in human brain studies. In a multicellular transwell model, amyloid beta exposure also triggers secretion of clinically relevant biomarkers, including p-tau217.

The lab is now extending this work into 3D systems, including a planned collaboration with 28bio to compare findings in triple-culture systems and brain organoids, with and without anti-amyloid therapies such as lecanemab.

Key Takeaways
‍

• AD-associated neurons show elevated synaptic activity and hyperexcitability that track with donor amyloid burden
• Amyloid beta drives cell type–specific responses across the neurovascular unit, with multicellular systems capturing clinically relevant biomarkers like p-tau217
• Upcoming collaboration applies CNS-3D Brain Organoids to Alzheimer's disease research alongside established 2D iPSC models

Speaker

Kellianne Alexander, PhD, Post-doctoral researcher, Harvard Medical School, Brigham and Women's Hospital

Kellianne Alexander is a postdoctoral fellow in the Pearse-Young lab. She is interested in studying the genetic and molecular mechanisms underlying hyperexcitability and synaptic vulnerability in Alzheimer’s Disease using human derived induced pluripotent stem cells (iPSCs).

‍