Rare genetic variation in fibronectin 1 (FN1) protects against APOE ε4 in Alzheimer’s disease

AbstractThe risk of developing Alzheimer ’s disease (AD) significantly increases in individuals carrying theAPOE ε4 allele. Elderly cognitively healthy individuals withAPOE ε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects ofAPOE ε4; however, these mechanisms are unknown. We hypothesized thatAPOE ε4 carriers without dementia might carry genetic variations that could protect them from developingAPOE ε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the 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 unaffectedAPOE ε4 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. An independent analysis in a large cohort of 7185A...
Source: Acta Neuropathologica - Category: Neurology Source Type: research