Apolipoprotein E in Alzheimer's disease trajectories and the next-generation clinical care pathway

  • Nat Neurosci. 2024 Jul;27(7):1236-1252. doi: 10.1038/s41593-024-01669-5.
Sneha Narasimhan  1 ,  David M Holtzman  2 ,  Liana G Apostolova  3  4  5 ,  Carlos Cruchaga  6  7 ,  Colin L Masters  8 ,  John Hardy  9 ,  Victor L Villemagne  10 ,  Joanne Bell  1 ,  Min Cho  1 ,  Harald Hampel  11
Affiliations
  • 1. Eisai Inc., Nutley, NJ, USA.
  • 2. Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University in St. Louis, St. Louis, MO, USA.
  • 3. Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 4. Department of Radiology and Imaging Neurosciences, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 5. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 6. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • 7. NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA.
  • 8. Florey Institute and the University of Melbourne, Parkville, Victoria, Australia.
  • 9. Department of Neurodegenerative Disease and Dementia Research Institute, Reta Lila Weston Research Laboratories, UCL Institute of Neurology, Queen Square, London, UK.
  • 10. Department of Psychiatry, the University of Pittsburgh, Pittsburgh, PA, USA.
  • 11. Eisai Inc., Nutley, NJ, USA. [email protected].
PMID: 38898183 DOI: 10.1038/s41593-024-01669-5
Abstract

Alzheimer's Disease (AD) is a complex, progressive primary Neurodegenerative Disease. Since pivotal genetic studies in 1993, the ε4 allele of the Apolipoprotein E gene (apoE ε4) has remained the strongest single genome-wide associated risk variant in AD. Scientific advances in apoE biology, AD pathophysiology and ApoE-targeted therapies have brought apoE to the forefront of research, with potential translation into routine AD clinical care. This contemporary Review will merge apoE research with the emerging AD clinical care pathway and discuss apoE genetic risk as a conduit to genomic-based precision medicine in AD, including ApoE's influence in the ATX(N) biomarker framework of AD. We summarize the evidence for apoE as an important modifier of AD clinical-biological trajectories. We then illustrate the utility of apoE testing and the future of ApoE-targeted therapies in the next-generation AD clinical-diagnostic pathway. With the emergence of new AD therapies, understanding how apoE modulates AD pathophysiology will become critical for personalized AD patient care.