Will Darrell Issa lose in 2018?

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I think it's more likely he retires and Applegate wins it in a relative walk.

I think Issa will run and lose. Will Applegate even run next year, or will it be some other Democrat?

Google is your friend.

I'm surprised he already announced running this early. What if some other Democrat advances to November and Applegate finishes third in the primary?

No other Democrat in the district exceeds Applegate's stature. Democrats have pretty much already coalesced around him, too. If I was to bet this far out, I think this district is on borrowed time for Republicans, whether Issa runs or not.

Democrats from other districts can run in CA-49. One can run in a district without living there as long as they live in the same state.

There's a reason why people rarely do that, though. It's much easier to get elected if you live in the district.