This is a good question: what happened to the Gen 4 ponies, and the Gen 5 was set like 1,000 years in the future?

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Best guess... The Mane 6 sans Twilight died, and though she tried to keep things together, Twilight just couldn't keep going with running the kingdom. Celestia and Luna had left their celestial bodies to try and lighten the workload, and Spike while still young for a dragon was now to big to be by her side as easily as before.
Eventually an event happened that caused Twilight to snap, either doing or saying something she shouldn't have. After tempers cooled and tensions fixed she decided to step back from ruling and put plans in place to eventually step down.
Unlike Celestia she didn't try to raise someone else to Alicorn hood and set in place a government composed from all tribes. Once finished she slowly removed herself from the public image until she disappeared entirely.
After a century or 2 however problems began to arise. Greedy ponies began to take office and use their positions for themselves. This leads to eventual conflict with other kingdoms, and with no-one able to calm all the tensions war eventually broke out.
Equestria was able to hold out for a long time. But eventually they lost. A result of this cause the the tribes to bicker amongst themselves and eventually split.
Finally due to the all the division and discourse over the recent years the Magic of Friendship, and by extension all Magic, disappeared from the Lands.

It's a good point. I'm curious about the whereabouts of the two alicorns, Luna and Celestia, Twilight, and Cadence. Not to mention, Cadance's daughter too. I've heard that Discord is still present in the comics. It feels like a millennium has gone by.