The complexity of Alzheimer's disease: an evolving puzzle

Physiol Rev. 2021 Jul 1;101(3):1047-1081. doi: 10.1152/physrev.00015.2020. Epub 2021 Jan 21.


The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end of the century to identify the components of pathological hallmarks and genetic subtypes and to formulate the first pathogenic hypothesis. Thanks to biomarkers and new technologies, the concept of AD then rapidly changed from a static view of an amnestic dementia of the presenium to a biological entity that could be clinically manifested as normal cognition or dementia of different types. What is clearly emerging from studies is that AD is heterogeneous in each aspect, such as amyloid composition, tau distribution, relation between amyloid and tau, clinical symptoms, and genetic background, and thus it is probably impossible to explain AD with a single pathological process. The scientific approach to AD suffers from chronological mismatches between clinical, pathological, and technological data, causing difficulty in conceiving diagnostic gold standards and in creating models for drug discovery and screening. A recent mathematical computer-based approach offers the opportunity to study AD in real life and to provide a new point of view and the final missing pieces of the AD puzzle.

Trial registration: NCT02293915.

Keywords: Alzheimer’s disease; amyloid; dementia; neurodegenerative disease.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / diagnosis*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Biomarkers / metabolism
  • Brain / metabolism
  • Brain / pathology*
  • Humans
  • Peptide Fragments / metabolism*
  • Plaque, Amyloid / diagnosis*
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology


  • Amyloid beta-Peptides
  • Biomarkers
  • Peptide Fragments

Associated data