Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease
Fecha
2024-03Autor
Bhattarai, Prabesh
Iniyan Gunasekaran, Tamil
Belloy, Michael E.
Reyes-Dumeyer, Dolly
Jülich, Dörthe
Tayran, Hüseyin
Yilmaz, Elanur
Flaherty, Delaney
Turgutalp, Bengisu
Sukumar, Gauthaman
Alba, Camille
Martínez McGrath, Elisa
Hupalo, Daniel N.
Bacikova, Dagmar
Le Guen, Yann
Lantigua, Rafael
Medrano, Martin
Rivera, Diones
Recio, Patricia
Nuriel, Tal
Ertekin-Taner, Nilüfer
Teich, Andrew F.
Dickson, Dennis W.
Holley, Scott
Greicius, Michael
Dalgard, Clifton L.
Zody, Michael
Mayeux, Richard
Kizil, Caghan
Vardarajan, Badri N.
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The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly
cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the
pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without
dementia might carry genetic variations that could protect them from developing APOEε4-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 unaffected APOEε4 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 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1
was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95%
CI [0.42, 6.32], P = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD.
Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less
reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of
APOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with
loss-of-function (LOF) mutations in fn1b—the ortholog for human FN1. We found that fibronectin LOF reduced gliosis,
enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of
FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition
of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing
novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.
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