Liara's timecapsules are obsolete, because obviously we won against the reapers in ME3.
I guess ME4 will be placed 100 years after ME3 or so, long enough to have Shepard dead, but not too long, because otherwise the setting is getting less interesting.
It will start off in our galaxy, because you need a connection to Earth somehow as an anchor.
Liara will probably even be alive still, maybe act as a matriach, so there's another reason you don't need timecapsules.
The new big enemy - probably another ancient super-race from another galaxy. My top pick.
Other options are the rachni, remaining reapers from dark space (less likely). I doubt Leviathans will be the enemy because of the boring underwater setting where they live, but maybe they turn out to be the controllers of the new enemies, aka the endboss.