Serena staying for Alola is at least more likely than Misty returning as a main character. If Misty hasn't returned for more than a decade, she most likely won't return now either. Writers could have her a cameo when Ash returned to home from Unova, but the writers blew it up. Shows to me the writers aren't very favourable towards Misty.
The difference here, however, is that unlike in Unova or even Kalos, Alola's going to be right at the start of the 20th anniversary of the Anime, and then there's the setting of Alola, which is more water-based than land-based (the last time we had a region like that was with Hoenn). Remember what Misty's type speciality and goal was? Water Pokémon Master. See where I'm getting at? Besides, I'm pretty sure even the Anime writers would want to make some degree of celebration for the occasion since most animes don't last as long as twenty years, and as such is truly a rare milestone to achieve (at least, that's what Famon claims). And then there's the fact that we're getting G.E.M. series figurines for the Original series versions of Ash AND Misty, and while Ash can be pointed to early Kanto due to the presence of Charmander, we can't say that Misty has a firm placement of which original series portion she is part of beyond being after Who Gets To Keep Togepi? because her Pokémon are Togepi and Psyduck in that figurine set. And let's not forget also that they're selling figurines of a character who by that point has been largely retired, which is unusual especially since the Pokémon merchandising generally doesn't even focus on old characters, not even during the 10th anniversary. And the figurines were just released, too early for it to be focusing on the Anime's 20th Anniversary (that's next year). Did I also mention that Brock isn't even part of that set even though he was a former main character and one of the original trio? And before you cite that Team Rocket got a G.E.M. figure, that at least can be assumed to be their Kalos selves, since, Best Wishes aside, Team Rocket are the only major characters to actually KEEP their outfits each series (not to mention their only consistent Pokémon besides Meowth, again, Best Wishes aside, was Wobbuffet), so that's not evidence against Misty returning, and if anything is even MORE reinforcement towards Misty's return.
And in all fairness to Unova and Misty being shafted, Unova itself was a mess, considering they turned Ash stupid, even by his usual standards, the fact that they kept Team Rocket inconsistent, and actually ruined a lot of potential for advertising Black 2 and White 2, oh, and gave Dawn an absolutely pointless cameo appearance. And I wouldn't say Misty was shafted that badly, considering that they DID have that Team Rocket Radio episode where Ash and Misty took over and they even promised that Misty would in fact return. We could even say the writers weren't very favorable to Ash considering just how shafted he was (he even did worse in that league than the prior one, something not even the Hoenn League, which until then was Ash's worst turnout ever, accomplished).
Besides, by that logic, Jessiebelle would have absolutely no reason to return in DP after her appearance in Kanto specifically BECAUSE it was over a decade later, yet last time I checked, not only did she return in DP (she even got a mention in the second episode of the series), but she even returned two years later right after the Cyrus incident in fact, and she had even LESS reason to reappear than Misty would right here. And don't forget Brock's Mom: She had only a token mention in Episode 5, and it was such a brief mention that 4Kids even claimed she was dead in that mention and left a later plothole later on when, whoops, she was alive all along, yet she then made her debut in the Hoso Specials, and later, Grating Places, five to nine years later, and then had a cameo in the ending to Movie 11. All of those were COTDs, which basically means they were not exactly meant to make more appearances, so if they could get reappearances even after more than a decade, Misty most certainly can, and unlike them, Misty's reappearance actually CAN be justified, via it being the 20th anniversary.
Either way, it's pretty clear Serena's going to leave (they couldn't keep Iris when they had the opportunity via it being a fresh start to do so, what makes you think that Serena could do it. And besides, isn't her goal to become Kalos Queen? No way she can do that while traveling with Ash to Alola).
EDIT: I might as well also add that her voice actress, Mayumi Iizuka, is still active in the industry, so there's also a little more evidence pointing towards it. Certainly, she has more of a chance of returning than May since her VA, KAORI, quit voice acting to pursue pop idol singing a'la Hillary Duff.
