The Amyloid-β Pathway in Alzheimer’s Disease
Harald Juergen Hampela b✉, John Hardyc, Kaj Blennowd e, Christopher Chenf, George L. Perryg, Seung Hyun Kimh i, Victor L. Villemagnej k, Paul S. S. Aisenl, Michele Vendruscolom, Takeshi Iwatsubon, Colin Louis Masterso,
- aEisai Inc., Neurology Business Group, Woodcliff Lake, NJ, USA. Harald_Hampel@eisai.com
- bEisai Inc., Neurology Business Group, Woodcliff Lake, NJ, USA
- cUK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK
- dClinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- eInstitute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- fMemory Aging and Cognition Centre, Departments of Pharmacology and Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- gDepartment of Biology and Neurosciences Institute, University of Texas at San Antonio (UTSA), San Antonio, TX, USA
- hDepartment of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea
- iCell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea
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Abstract
Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.