Dissecting the role of LAMA1 genetic variant in modulating blood-brain barrier integrity and protection against APOE4-driven Alzheimer's disease

Alzheimer’s disease (AD) is marked by progressive cognitive decline and blood-brain barrier (BBB) breakdown, especially in individuals carrying the high-risk APOEε4 genotype. Yet, some APOEε4 homozygotes remain cognitively intact, suggesting the presence of genetic resilience mechanisms. Through whole-genome sequencing of resilient APOEε4 carriers, we identified a rare protective missense variant in LAMA1 (G967D), a key laminin subunit critical for BBB integrity. We hypothesize that this LAMA1 variant modifies extracellular matrix (ECM) composition, mitigating BBB dysfunction. In Aim 1, we will generate the LAMA1 variant in human iPSC- derived astrocyte-endothelial co-cultures within 3D hydrogels and assess ECM remodeling and proteomic changes. In Aim 2, we will use CRISPR-edited APOEε4 zebrafish models to examine the in vivo impact of orthologous LAMA1 genetic variant on BBB dysfunction, vessel leakage, gliosis, and gene expression in BBB cell types. By integrating human and zebrafish models with imaging, single-cell transcriptomics, and proteomics, this project will provide novel mechanistic understanding of LAMA1 genetic variant and its therapeutic potential for maintaining BBB homeostasis in genetically at-risk populations. Project Number: 1R21NS149249-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Caghan Kizil | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $452,375 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BN-E (91)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11351607