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Alice Howland, a linguistics professor at Columbia University, celebrates her 50th birthday with her physician husband John and three adult children. Giving a lecture, Alice forgets the word "lexicon", and during a jog becomes lost on campus. Her doctor diagnoses her with early onset familial Alzheimer's disease.
Alice's eldest daughter, Anna, tests positive for the Alzheimer's gene. Anna's unborn twins test negative, as does Alice's son Tom. Alice's younger daughter, aspiring actress Lydia, decides not to be tested.
As Alice's memory begins to fade, she daydreams of her mother and sister, who died in a car crash when she was a teenager. She memorizes words and sets a series of personal questions on her phone, which she answers every morning. She hides sleeping pills in her room, and records a video message instructing her future self to commit suicide with the pills when she can no longer answer the questions. As her disease advances, she becomes unable to give focused lectures and loses her job. She becomes lost searching for the bathroom in her own home and wets herself, and does not recognize Lydia after seeing her perform in a play.
John is offered a job at the Mayo Clinic in Minnesota. Alice asks him to postpone it, but he feels this is impossible. At her doctor's suggestion, Alice delivers a speech at an Alzheimer's conference about her experience with the disease, using a highlighter to remind herself which parts of the speech she has already spoken, and receives a standing ovation.
Alice begins to have difficulty answering her phone questions. She loses the phone, causing her anxiety; John finds it a month later in the freezer, but Alice thinks it was only missing for a day. She visits Anna in the hospital to meet her newborn twin grandchildren, but does not recognize her daughter.
After a video call with Lydia, Alice inadvertently opens the video with the suicide instructions. With some difficulty, she finds the pills and is about to swallow them, but when she is interrupted by the arrival of her caregiver she drops the pills on the floor, quickly forgetting her suicide plan.
John resolves to move to Minnesota and Lydia moves back from California to care for Alice. Lydia reads her a section of the play Angels in America and asks her what she thinks it is about. Alice, now barely able to speak, responds with a single word: love.