Whenever I do a new install, I delete every file and folder except 'Settings', so, obviously, my settings are kept.
This means my Framelock, HB placement, bot specific (Fx Enyo), CR specific etc settings stays, but CompiledAssemblies, Cache and all other system files are renewed.
And because I do it in the same folder, Windows keeps my Run As Administrator checked for Honorbuddy.exe and so on.
Regarding:
It does make a lot of sense. The closest I can compare it to is updating firmware on a router. Even though there's an "auto updater", a lot of settings are kept that related to the old firmware, which may have changed to the new firmware. So doing an NVRAM clear and factory reset is a good idea. But not needed if you go one version up, however if you have an old installation..
Which might contradict what I said first, but I re-do my settings (can do it in 2 mins, gotten pretty good at it

) every now and then.
TL;DR: There are many settings you don't see in the GUI, which can cause issues.
Contributing to the thread:
Set your Framelock (Settings & Tools) to your lowest FPS. Mine's a 45, because that's the lowest I will dip to during raids with everything on Ultra.
Look for plugins, many are useful. Examples I use most: Disenchantix and LogMeOut (great paired with HBRelog/ARelog). I don't use ItemRemover or TidyBags, but they deserve honorable mention

Like Untg, I've set my Battle.net client to shut down after game launch, so it doesn't sit there detecting my haxx all day long.
I have yet to set up a truly AFK bot, but I can feel I'm getting close, and it's definitely my goal - as it's the purpose of botting.