For a while I ran a setup where I did all of my work in a local tmux session, but part of this work involved SSH-ing and attaching to a screen session.
When using both, especially nested, I found it beneficial to have a different leader for each.
I also use <^-a> to go to the start of the line, so I'd miss that.
1. I can still use C-a with readline (go to first character)
2. If I ssh and then use screen, I can use C-a to navigate my remote screen and C-s to navigate my local tmux.
3. C-s is closer to C-a then other letters on my keyboard.