Abstract
Neurodegenerative diseases overwhelmingly impact individuals in old age, yet most disease models rely on rare genetic variants in transgenic animals or iPSC-derivedneurons whose rejuvenated state fails to mirror adult and aged cell types, which is limiting insight into the complexities of human brain aging.
By directly converting patient fibroblasts into induced neurons (iNs), we preserve donor-specific age-related cellular traits, making iNs a unique tool for modeling authentic human brain aging and age-dependent disease. In our recent work using iNs to model the cellular trajectory from healthy aging through mild cognitive impairment (MCI) to Alzheimer's disease (AD). Across a cohort of healthy aging and MCI/AD donors, we find that MCI is not simply a milder or intermediate form of AD, but a qualitatively distinct, transient pathogenic state: MCI iNs display accelerated epigenetic aging, non-monotonic transcriptional modules driving inflammatory signaling and synaptic hyperactivity, and functional elevated neuronal activity, and smoldering inflammatory secretome thatconditions human iPSC-derived microglia. Acute neuronal hyperexcitation, modeling seizure-like events seen in early AD patients, converts this latent state into an overt disease-associated microglial program, revealing functional convergence of neuronal hyperactivity and neuroinflammation at the MCI stage. In summary, these findings demonstrate that iNs reflect donor-specific aging biology and disease stage, providing a human patient-specific model to uncover early, and potentially reversible drivers of neurodegeneration.

Biography
Jerome Mertens is Associate Professor and Riford Chair for Neurodegenerative Disease and Dementia at UC San Diego’s Department of Neurosciences, and Adjunct at the Salk Institute. He earned his PhD at the University of Bonn, training with Oliver Brüstle, followed by postdoctoral research with Rusty Gage at Salk. Dr. Mertens’ lab models human brain aging and neurodegenerative disorders using patient-specific cellreprogramming. By directly converting human fibroblasts into induced neurons (iNs), the lab preserves donor aging signatures, and contrasts this with rejuvenated iPSC-based models. Integrating iN and iPSC approaches with functional genetics, next-generationsequencing, and multi-omics techniques, his team aims to unravel how genetic and non-genetic cellular changes drive age-related brain disease pathways.