My money(though it will be worthless long before I can collect) is on a plague of some sort, a viral threat that spreads at the speed of culture. Every civilization in history has been defeated, ultimately, by population loss due to parasitical infection. For more, read William MacNeill's excellent 'Plagues and Peoples' (1976) or the much more wry 'Rats, Lice and History' (I forget the Author's name). I really like how MacNeill refers to forms of government as "macroparasites".

I've been thinking about the merging of human and artificial intelligences. Eventually, we may have internal augmentation. Chips for everything from ID purposes to increased metabolism to turning on our steros by thought alone (like a high-tech version of the Clapper). That one has had some recent successes in chimp brains, by the way.
Anyhow, at that point, computer viruses will be as volatile as organic ones. And will be able to spread not at the speed of a jet or car, but the speed of the electron.

Of course, in the midst of a plague-induced collapse, it's perfectly likely that a few of the nastier weapons of war might be launched in a final hurrah.