Rare genetic variation in Fibronectin 1 (FN1) protects against APOEe4 in Alzheimer's disease

摘要: The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying the APOEe4 allele. Elderly cognitively healthy individuals with APOEe4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEe4; however, these mechanisms are unknown. We hypothesized that AAPOEe4 carriers without dementia might carry genetic variations that could protect them from developing APOEe4-mediated AD pathology. To test this, we leveraged whole genome sequencing (WGS) data in National Institute on Aging Alzheimer's Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEe4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood-brain barrier (BBB), for postmortem validation and in vivo functional studies. The FN1 and COL6A2 protein levels were increased at the BBB in APOE ϵ4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEe4 carriers had significantly lower FN1 deposition and …