The changes to the setting are pretty massive:
Large portions of the world are simply no longer there. Excised. Deleted. Choose your verb. The old kingdom nation of Mulhorand is gone, literally ripped out of the world and no longer part of the planet. Unther was likewise removed, and transplanted in its place is an entire kingdom of dragonborn, presumably to bring that
4e race into the Realms where they hadn't existed previously. Thay is decimated and a big, undead wasteland.
Further south, the nation of Halruaa was obliterated by the Spellplague and it and its civilization no longer exist for all intents and purposes.
A lot of the map was ravaged in order to make
FR fit the PoL dynamic. And due to the huge time-jump between the end of
3e and the start of the
4e Realms, unless a character was immortal or perhaps a very long-lived elf, they're going to be dead, so a lot of plot hooks and developing metaplot is rather abruptly gone.
The biggest impact on PCs however is that because of the timejump and the slew of changes, there's no easy way to transition PCs from a
3e FR campaign into a
4e one. Most PCs would die during the time interval, and the world is so different, they might not recognize it, and anything they'd worked for, protected, built up, etc likely isn't around anymore.
The
4e Realms
IMHO can work if you're starting a fresh campaign with little or no connection to prior material (some was retconned, some was never touched on in
4e, much was made moot due to other changes and the timejump). The
4e Realms are effectively a new campaign setting compared to the 1e/2e/
3e Realms.
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