Alzheimer's disease: a jigsaw puzzle comprised of different types of programmed cell death pieces.

Alzheimer's disease (AD), a prevalent neurodegenerative disorder among elderly populations, arises from complex interactions between genetic and environmental risk factors. Currently affecting over 55 million elderly individuals globally, AD cases are projected to reach approximately 150 million by 2050 due to demographic aging trends. AD is characterized by extracellular accumulated amyloid plaques (Aβ plaques), intracellular aggregated neurofibrillary tangles (NFTs), and extensive neurodegeneration caused by neuronal and neural cell death. Many investigations have proven assorted types of programmed cell death (PCD) contribute to the neurodegenerative process of AD, and many review articles have summarized the role of PCD in AD pathogenesis. While numerous experimental studies have demonstrated the involvement of various programmed cell death (PCD) pathways in Alzheimer's disease (AD) pathogenesis, existing review articles lack comprehensive mechanistic integration. This review systematically evaluates all PCD-AD associations, including apoptosis, autophagy, necroptosis, parthanatos, phagoptosis, pyroptosis, NETosis, ferroptosis, and cuproptosis. Different from other existing reviews, this paper emphasizes that the pathogenesis of AD results from the combined involvement of multiple types of PCD (programmed cell death), rather than isolated pathways. Additionally, the roles of valence-variable metal ions in the pathogenesis of AD are also discussed.