A new drug target for Alzheimer's

Discovery of FN1 as a modifier gene for APOE4-mediated Alzheimer's pathology

The year 2024 just started, and new discoveries are already dropping in. A new preprint by Bhattarai, Gunasekaran, et al. reports the discovery of a new APOE4 modifier gene—FN1 (encodes fibronectin 1, an extracellular matrix protein).

Discovering modifier variants has been a major interest recently in the human genetics field, particularly in the Alzheimer’s field, as you may have read from my 2023 human genetics roundup.

I think the whole game of hunting for protective angel mutations among elderly cognitively healthy individuals carrying a known genetic risk factor for Alzheimer’s started in 2019 when a Nature Medicine paper reported about an elderly Columbian woman who stunned the scientists by defying the extremely high odds of developing Alzheimer’s at an early age due to PSEN1 mutation (causes early onset Alzheimer’s disease) that she was born with. She was found to be homozygous for an extremely rare form of APOE variant called the Christchurch variant. Last year, a paper in Nature Neuroscience showed that artificially introducing the Christchurch mutation in APOE4 mice and human iPSC models conferred protection against Alzheimer's pathology.

Last year, there was also another paper in Nature Medicine about a second superhuman from the Columbian early-onset Alzheimer's cohort, a male cognitively healthy at age 76, despite having been born with a PSEN1 mutation. He seemed to carry a different modifier mutation than the previous case--a gain of function mutation in RELN that encodes a protein that binds to some of the same receptors that APOE binds to.

Then finally, in a preprint from last year, Stanford researchers reported that individuals who carried both APOE loss of function variant and E4 missense variants in the same haplotype rarely developed Alzheimer’s, which spurred a lot of interest in the field as the finding supported allele-specifically inhibiting APOE as a way to treat Alzheimer’s caused by APOE4 risk factor.

In the current preprint, researchers from Columbia University report that individuals who carry APOE4 risk haplotypes might be protected from developing Alzheimer’s if they also carry any deleterious mutation in FN1. The genetic experiment is just eyeballing based on a prior hypothesis as I don’t see any statistical tests being reported for the enrichment of FN1 mutations among cases. However, the downstream functional analyses seem promising.

The authors looked in the post-mortem brains of Alzheimer’s cases and controls and showed that FN1 is upregulated in the blood-brain barrier (BBB) basement membrane (one of the sites where E4 pathogenesis is believed to happen) with a dose-response relationship between E4 allele dosage and FN1 expression. Again, at this point, the missense variants that led the authors to this FN1 gene went out of sight. It’s not clear what the BBB basement membrane of E4 carriers with FN1 missense variants will look like. Further, the authors also knocked out FN1 homolog in amyloid-toxicity zebra fish models and showed that FN1 deletion reduces abeta42-mediated toxicity.

It seems FN1 has been known to be bad for blood vessels and previously, serum FN1 levels were reported to be elevated in Alzheimer’s cases compared to controls, suggesting that FN1 might as well be a biomarker of Alzheimer’s disease progression. The authors speculate mutations in other genes part of the extracellular matrix components might also offer protection to Alzheimer’s through a shared biological mechanism with FN1.

Very interesting work with promising functional analyses, though we’d have to wait and see if FN1 turns out to be a true Alzheimer’s target. Below is a schematic abstract from the authors illustrating the protective effect of FN1 loss of function on APOE4 pathology.

Figure 7 from the preprint

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