Pathogen-associated molecular patterns (PAMPs) and endogenous “danger” signals, known as danger-associated molecular patterns (DAMPs), released from cells alert the innate immune system and activate several signal transduction pathways through interactions with the highly conserved pattern recognition receptors (PRRs). Both PAMPs and DAMPs directly induce proinflammatory cascades and trigger the formation of the inflammasome, mediating the release of cytokines. Here, we highlight the role of DAMPs, including amyloid β (Aβ), high-mobility group box 1 (HMGB1), the S100 family proteins, chromogranin A, and nucleic acids, in the innate-immune activation during the course of Alzheimer disease (AD), the most frequent neurodegenerative disorder.