Dr. Alice Howland (Julianne Moore), a linguistics professor at Columbia University, celebrates her fiftieth birthday with her physician husband John (Alec Baldwin) and three adult children. During 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 (Kate Bosworth), tests positive for the Alzheimer's gene; Anna's unborn twins test negative, as does Alice's son Tom (Hunter Parrish), a junior doctor. Alice's youngest daughter, aspiring actress Lydia (Kristen Stewart), decides not to be tested.
Alice memorizes words that she writes on a blackboard and sets herself personal questions on her phone that she answers every morning. She hides sleeping pills in her room and records a video message instructing her future self to commit suicide when she can no longer answer the questions. As her disease advances, she loses her job, unable to give focused lectures. 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 or spelling them correctly. She loses her phone, causing her anxiety; her husband finds it a month later. Alice 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 is interrupted by the arrival of her carer and spills the sleeping pills.
John resolves to move to Minnesota and Lydia moves back from California to care for her worsening mother. Lydia reads Alice a section of the play Angels in America and asks her mother what she thinks it is about. Alice, now barely able to speak, responds with a single word: love.