Lore wise things have gotten to out of hand. We're 200 years out and industrialism is trying to make a comeback on the West Coast. Furthermore the DLC have introduced post scarcity machines such as the Vending Machines. At this point the game has changed from Post-Apocalypse to the words of Chris Avellone "Post-Post Apocalypse which is why they nuked the civilizations again in Lonesome Road. This is gone to far, either A. We are going to continue to see industrialism almost start then fail or B. We have to keep playing Capital Wastelands. Once you add in super advanced tech like Dead Money or The Institute you have the possibility of just breaking the whole reason for the game world.
I suggest Fallout 4 simply restarts. Follow Fallout 3's lead and start the game has a child that ages throughout the story, the only difference being that you don't grow up in the secure location of the vault but rather in the dangerous waste. I would further suggest setting the game immediately after the Great War if not somewhat before for the exposition and use the Pre War world as a chance to get the tutorial things out of the way all the while making us care about our characters struggle.
Most Fallout fans who have never played 1 or 2 don't know the lore. Why not simply start over and reintroduce these concepts to this new audience? The plot ideas become very easy once we stop remembering the old static factions and events of the past.
Secondly the mechanics of the game need to change. I love the Pip Boy Interface but the game engine Fallout currently uses needs to go the way of the dodo. Fallout 4 should take the mold of Far Cry/Red Dead Redemption in it's presentation. I say Far Cry for it's amazing 1st person effects and Red Dead for it's almost mastery of the 3rd person camera. Furthermore with new lore there's no reason why we can't have horses to ride, cars to drive or planes to fly. If the game takes place right after the Great War then all of those things would be possible sense the plastic and oil needed wouldn't be gone yet.
Can you imagine it? Riding your trusty steed over the deserted semi-arid plains of Kansas as the sun sets and you grip onto your M16 that only has 3 bullets remaining...