Big ones? The structure of the game hasn't changed too much in the past two years (in comparison to if you quit in S1 and came back in S3).
-They redid the jungle again, so you'll need to do a couple custom games to get used to it. There's a mini-Baron ("Rift Herald"), the dragon got changed to a bunch of different dragons, and almost all the little camps have been redone (and they added a couple).
-Boot enchants are gone.
-Flat Armor Pen got replaced with "Lethality". It's like Flat Armor Pen, but it scales with your level, so it's weaker early and stronger late.
-Two important (high play rate) champs have come out since S4, Ekko and Jhin.
-Masteries changed (as they almost always do). The important thing now is the "keystone" mastery (the one you put the 18th point in a tree into). You'll need to learn what these do, as they can have significant impact on in-game play (like a shield for 35% of health upon doing hard CC, or gaining 75% slow immunity for 10 seconds).