The article discusses the development of new precision medicine approaches for the prevention of Alzheimer's disease (AD) by focusing on the structure and function of γ-secretases. It highlights the limitations of anti-amyloid antibody therapies and introduces γ-secretase allosteric stabilizers (GSAS) as a more targeted approach. GSASs stabilize the enzyme-substrate complex, increasing the processivity of substrate cleavage and altering the size spectrum of Aβ peptides. This mechanism is distinct from γ-secretase modulators (GSM), which are less selective. GSASs are proposed as a precision medicine strategy to prevent amyloid deposition by specifically targeting a discrete aspect of the complex cell biological signaling mechanism that initiates AD pathology. The article reviews the structure and function of γ-secretases, emphasizing the role of presenilin (PSEN) mutations in early-onset AD. It discusses the challenges of γ-secretase inhibitors (GSI), including their broad effects on multiple substrates and adverse side effects. GSASs are considered more promising as they maintain normal physiological processing of substrates while enhancing Aβ cleavage to favor shorter peptides. The article also explores the structural insights into γ-secretases, the role of PSEN mutations in AD, and the potential of GSASs in AD prevention. It concludes that GSASs offer a more targeted approach to AD prevention by stabilizing the enzyme-substrate complex and altering Aβ production, potentially reducing the risk of amyloid aggregation and neurodegeneration.The article discusses the development of new precision medicine approaches for the prevention of Alzheimer's disease (AD) by focusing on the structure and function of γ-secretases. It highlights the limitations of anti-amyloid antibody therapies and introduces γ-secretase allosteric stabilizers (GSAS) as a more targeted approach. GSASs stabilize the enzyme-substrate complex, increasing the processivity of substrate cleavage and altering the size spectrum of Aβ peptides. This mechanism is distinct from γ-secretase modulators (GSM), which are less selective. GSASs are proposed as a precision medicine strategy to prevent amyloid deposition by specifically targeting a discrete aspect of the complex cell biological signaling mechanism that initiates AD pathology. The article reviews the structure and function of γ-secretases, emphasizing the role of presenilin (PSEN) mutations in early-onset AD. It discusses the challenges of γ-secretase inhibitors (GSI), including their broad effects on multiple substrates and adverse side effects. GSASs are considered more promising as they maintain normal physiological processing of substrates while enhancing Aβ cleavage to favor shorter peptides. The article also explores the structural insights into γ-secretases, the role of PSEN mutations in AD, and the potential of GSASs in AD prevention. It concludes that GSASs offer a more targeted approach to AD prevention by stabilizing the enzyme-substrate complex and altering Aβ production, potentially reducing the risk of amyloid aggregation and neurodegeneration.