First, Hotaru's older brother telling her that he really does love her, and he never forgot about her like she assumed he did.
Then, the main characters go back in time to observe how Mikan's parents met. This culminates in her father's violent death orchestrated by the Big Bad, accidentally caused by Serio aka Persona, a boy he essentially helped raise.
Before this, Mikan seeing his death coming, jumping into the period of time shortly before from the window she and the group were observing from. The way she called out for him and tried to warn him before getting pulled back by Tsubasa was particularly gut-wrenching.]
[Then, flash forward nine months, to Mikan's birth, and a daydream/vision of her father's ghost holding the baby he never even knew was conceived. "Look, Yuka, it's a girl! She's so beautiful... Our Mikan..." SOB.
The Hope Spot from the penultimate arc. When Mikan and co. were about to use the warphole that would lead her and her mother Yuka out, it's revealed the key they were holding was a dud, causing an explosion that Yuka shields Narumi from, killing her in the process. Right in front of Mikan, who just finally met her mother and had the chance to live with her...
The final arc. Mikan's attempt to save Natsume reveals that her Alice is the type that depletes and ends up running out. Because of this, the school's policy is to release her. Moreover, due to her being the daughter of two people especially connected to the school, it's decided the safest countermeasure against kidnappers and other enemies of the academy is to ERASE ALL OF HER MEMORIES of Alice Academy (her friends, her guardians, her PARENTS). Even poor Bear is depressed by this, to the point he tagged along with her when she finally went home.
It gets even worse when Hotaru decides to save Natsume for Mikan and goes back in time to the point where he was injured in with Nodacchi and Subaru. The punishment for screwing destiny and saving his life is that the Imai siblings disappear into time and space and are slowly forgotten by everyone. Hotaru's last act before disappearing is to give Mikan one last visit, the night before she had to leave Alice Academy. Remember when this story was happy?