Dennis J. Selkoe reviews the progress in understanding Alzheimer's disease (AD) over the past three decades, highlighting the role of protein misfolding and aggregation in neurodegenerative disorders. AD is characterized by the accumulation of amyloid β-protein (Aβ) in extracellular plaques and hyperphosphorylated tau in intracellular neurofibrillary tangles. These pathological features have been central to understanding the disease's molecular mechanisms and have led to the identification of genetic factors contributing to AD. The study of familial AD has shown that mutations in genes encoding Aβ and tau lead to the misfolding and aggregation of these proteins, which are potential therapeutic targets. The article discusses the biochemical nature of the diagnostic brain lesions, the generation of Aβ through regulated proteolysis of the β-amyloid precursor protein (APP), and the genetics of AD, including the role of the apolipoprotein E (ApoE) ε4 allele. It also explores the genotype-to-phenotype relationships in familial AD, the use of genetically engineered mouse models to study AD, and the emerging therapeutic opportunities, including inhibitors of Aβ production, anti-aggregating agents, and immunotherapy. The article concludes with the potential for future risk-assessment profiles and preventative treatments for AD.Dennis J. Selkoe reviews the progress in understanding Alzheimer's disease (AD) over the past three decades, highlighting the role of protein misfolding and aggregation in neurodegenerative disorders. AD is characterized by the accumulation of amyloid β-protein (Aβ) in extracellular plaques and hyperphosphorylated tau in intracellular neurofibrillary tangles. These pathological features have been central to understanding the disease's molecular mechanisms and have led to the identification of genetic factors contributing to AD. The study of familial AD has shown that mutations in genes encoding Aβ and tau lead to the misfolding and aggregation of these proteins, which are potential therapeutic targets. The article discusses the biochemical nature of the diagnostic brain lesions, the generation of Aβ through regulated proteolysis of the β-amyloid precursor protein (APP), and the genetics of AD, including the role of the apolipoprotein E (ApoE) ε4 allele. It also explores the genotype-to-phenotype relationships in familial AD, the use of genetically engineered mouse models to study AD, and the emerging therapeutic opportunities, including inhibitors of Aβ production, anti-aggregating agents, and immunotherapy. The article concludes with the potential for future risk-assessment profiles and preventative treatments for AD.