Y'know, I kind of went this route in 3e when I did my Cthulu Comes To Town campaign.
I can't tell you how AMAZING it was. It started off as a bit of a lark. I read the FRCS for the first time in 3e, and it already stuck me as too thick with people who have already accomplished greatness to let my players truly shine where they should. Without me somehow tricking my way out of having the Big Brothers of the setting show up and save the day, it was pretty much un-usable.
So I hit it with Cthulu. One of the central tenets of magic in the Mythos setting is that it is dangerous and it will drive you mad. So, suddenly, everything magical was dangerous. FR is a realm of high magic, and once that magic becomes pernicious, predatory, and harmful, a lot of FR starts to come apart at the seams.
I reveled in it. Everyone who knew magic became insane, weak, or dead. I had a VERY good explanation for why the Big Brothers didn't show up.
And the PC's were left to clean up the mess and restore some semblance of order.
What FR has been lacking for all of 3e has been a great, devouring danger, one that can be avoided but never confronted directly, one that magic fails to make safe.
I gave it this with Cthulu.
The 4e team, following my model (I can only assume, with my massive ego, that I gave them the idea.

), went with the Spellplague.
A bit more authentic, a bit less tongue-in-cheek, but the same end result:
NOTHING is safe anymore.
Elminster, the Biggest of the Big Brothers, isn't capable of defending the universe.
Mystra (and the Weave) is dead and broken into a million pieces. Her help is not reliable.
The rest of the Chosen are all varying degrees of insane zombie monsters.
This is fun, this is inspiring, this is a setting in need of heroes.
3e FR doesn't need heroes. If any villain gets TOO troublesome, Elminster will handle it.
4e restores, but hook, crook, and Spellplague, the need for heroes in the setting.
This is the shot in the arm that the setting needs to be playable.
It's the end of the world as we know it, and I feel fine.