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Deciphering the mechanism underlying late-onset Alzheimer disease

Nature Reviews Neurology volume 9, pages 25–34 (2013)Cite this article

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Abstract

Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.

Key Points

  • Despite tremendous investments in basic and clinical research, no cure or preventive treatment for Alzheimer disease (AD) exists

  • A re-evaluation of the current view of the mechanisms underlying late-onset AD pathology is a prerequisite for future translational approaches

  • Inflammatory processes are strongly correlated with AD onset and progression in humans, and could have a pivotal role in disease aetiology

  • Chronic inflammation coupled with neuronal ageing induces cellular stress and concomitant impairments in basic neuronal functions

  • Inflammation-induced hyperphosphorylation and missorting of tau might represent one of the earliest neuropathological changes in late-onset AD

  • Molecular changes underlying late-onset AD involve impairments in cytoskeleton stability and axonal transport, which could trigger axonal degeneration and formation of senile plaques and neurofibrillary tangles, resulting in neuronal death

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Figure 1: The inflammation hypothesis of late-onset Alzheimer disease.
Figure 2: Axonal swellings and leakage as a trigger of senile plaque formation in patients with Alzheimer disease.

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Acknowledgements

This study was supported by the Swiss National Science Foundation, grant number 310030-132629, the Gottfried und Julia Bangerter-Rhyner Foundation, and the Olga Mayenfisch Foundation.

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  1. Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland

    Dimitrije Krstic & Irene Knuesel

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Both authors contributed to researching data for the article, discussions of the content, writing the article and to review and/or editing of the manuscript before submission.

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Correspondence to Irene Knuesel.

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Krstic, D., Knuesel, I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat Rev Neurol 9, 25–34 (2013). https://doi.org/10.1038/nrneurol.2012.236

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