I think the only things which could greatly impact football's popularity are...
1) If the fear of concussions really changes the participation levels...
2) And if the product on the field (rules, talent) is changed enough that the game becomes less recognizable...
I've thought for a while that the former is the single biggest existential threat to the future of the NFL.
You don't have to play a sport growing up to appreciate it (I never played a down of organized football) but it helps. And, of course, it creates the talent pool for the next generation of players. If that talent pool starts to dry up, the league is going to come down to earth.
Now, I don't think that it would be enough to kill the sport. But think of where baseball is now compared to 50 years ago, in terms of youth participation and an aging fanbase, and realize that baseball doesn't have the moral issues (or at least as many) around fandom and also has an international talent pool to draw from that the NFL has never successfully tapped despite several attempts. I can see (and think the NFL does, too) a time where they are no longer the dominant force in pro sports, even if they may still technically be #1.