Application of Systems Theory in Longitudinal Studies on the Origin and Progression of Alzheimer’s Disease

  • Simone Lista
  • Zaven S. Khachaturian
  • Dan Rujescu
  • Francesco Garaci
  • Bruno Dubois
  • Harald Hampel
Part of the Methods in Molecular Biology book series (MIMB, volume 1303)


This chapter questions the prevailing “implicit” assumption that molecular mechanisms and the biological phenotype of dominantly inherited early-onset alzheimer’s disease (EOAD) could serve as a linear model to study the pathogenesis of sporadic late-onset alzheimer’s disease (LOAD). Now there is growing evidence to suggest that such reductionism may not be warranted; these suppositions are not adequate to explain the molecular complexities of LOAD. For example, the failure of some recent amyloid-centric clinical trials, which were largely based on the extrapolations from EOAD biological phenotypes to the molecular mechanisms in the pathogenesis of LOAD, might be due to such false assumptions. The distinct difference in the biology of LOAD and EOAD is underscored by the presence of EOAD cases without evidence of familial clustering or Mendelian transmission and, conversely, the discovery and frequent reports of such clustering and transmission patterns in LOAD cases. The primary thesis of this chapter is that a radically different way of thinking is required for comprehensive explanations regarding the distinct complexities in the molecular pathogenesis of inherited and sporadic forms of Alzheimer’s disease (AD). We propose using longitudinal analytical methods and the paradigm of systems biology (using transcriptomics, proteomics, metabolomics, and lipidomics) to provide us a more comprehensive insight into the lifelong origin and progression of different molecular mechanisms and neurodegeneration. Such studies should aim to clarify the role of specific pathophysiological and signaling pathways such as neuroinflammation, altered lipid metabolism, apoptosis, oxidative stress, tau hyperphosphorylation, protein misfolding, tangle formation, and amyloidogenic cascade leading to overproduction and reduced clearance of aggregating amyloid-beta (Aβ) species. A more complete understanding of the distinct difference in molecular mechanisms, signaling pathways, as well as comparability of the various forms of AD is of paramount importance. The development of knowledge and technologies for early detection and characterization of the disease across all stages will improve the predictions regarding the course of the disease, prognosis, and response to treatment. No doubt such advances will have a significant impact on the clinical management of both EOAD and LOAD patients. The approach propped here, combining longitudinal studies with the systems biology paradigm, will create a more effective and comprehensive framework for development of prevention therapies in AD.

Key words

Early-onset alzheimer’s disease Late-onset alzheimer’s disease Sporadic Alzheimer’s disease Longitudinal studies Systems biology Transcriptomics Proteomics Metabolomics Lipidomics Biological markers 



HH and BD would like to thank for the support of the Fondation Pour La Recherche Sur Alzheimer (FRA), Paris, France.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Simone Lista
    • 1
  • Zaven S. Khachaturian
    • 2
  • Dan Rujescu
    • 1
  • Francesco Garaci
    • 3
    • 4
  • Bruno Dubois
    • 5
  • Harald Hampel
    • 5
  1. 1.Department of Psychiatry, Psychotherapy and PsychosomaticsMartin-Luther-University Halle-WittenbergHalle (Saale)Germany
  2. 2.The Campaign to Prevent Alzheimer’s Disease by 2020 (PAD2020)PotomacUSA
  3. 3.Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology, and RadiotherapyUniversity of Rome “Tor Vergata”RomeItaly
  4. 4.IRCCS San Raffaele Pisana, Rome and San Raffaele CassinoCassinoItaly
  5. 5.Département de Neurologie, Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A), Pavillon François Lhermitte, Hôpital de la SalpêtrièreUniversité Pierre et Marie CurieParisFrance

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