So the first time I installed the hotfix, it would always find new updates no matter how many times I re-installed, so I uninstalled it completely before trying again. I also decided to start fresh and removed all of my existing profiles.
After that, game profiles just stopped actually saving settings. I did a little snooping around in gmdb.blb, and found that it will add the game to the file no problem. The issue is that it doesn't enable it (profileEnabled is always FALSE) or save any settings whatsoever. I figured it might store the settings in memory and tried launching a game with a custom profile, and sure enough, the settings did not in fact work. After rebooting, the profile is still there, but disabled and without any of my changes.
I tried manually modifying the file to force profileEnabled to TRUE, and it will see that it's enabled, but it still won't save any changes regardless.
Finally I grabbed cnext.exe and cncmd.exe from a system restore, and it seems as though the newer binaries aren't reading from or writing to %localappdata%\ATI\ACE\APL\User.blb. After I figured that out, I restored the newer binaries again and found that it was trying to read/write to C:\WINDOWS\system32\atiapfxx.blb, (which it had no permission to, so I changed the permissions to allow it), in addition to the previously mentioned User.blb. After all of that, custom profiles work, but only for programs that I added manually. Anything added automatically using the "scan" functionality still doesn't save settings.
It might have been that User.blb or that weird system32 one were missing and it didn't create them, I don't know. Did not expect to spend my morning debugging my graphics control panel, so I'll let you guys (hopefully) handle it from here. Submitted a proper bug report.
Edit: Clarified a few details.