Hello
I am back with good news - I was able to fix my Problem.
After another year of frustrating manual installation of Plex, i was trying to find a solution again. I stumbled about a Post of @sa2000 (His Post)
What was especially helping me was, that i didnt knew of HKEY_USERS\.DEFAULT\Software\Plex, Inc.\Plex Media Server
I was just only familiar with following Location (that i was changing but didn’t resolve my Problem)
HKEY_CURRENT_USER\Software\Plex, Inc.\Plex Media Server
So I just made sure that both are pointing to my ../../Plex Media Server Directory. (Which in my case pointed to different locations. One pointed to somewhere on C:\ and the other one to E:\
After the change i tried the auto update function again and it worked - for the first time in about 3 years.
TL;DR: E.g. In case your Plex Media Server looks like:
E:\Plex\Plex Media Server\Cache
E:\Plex\Plex Media Server\Codecs
E:\Plex\Plex Media Server\Crash Reports
...
Make sure to put the following value
E:\Plex\
into both registry keys:
HKEY_USERS\.DEFAULT\Software\Plex, Inc.\Plex Media Server
HKEY_CURRENT_USER\Software\Plex, Inc.\Plex Media Server
A BIG thankyou to you @sa2000 you finally (not intended in first place) fixed my Porblem and the one of many others 
