Review Article | Published:

Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

Nature Reviews Neurosciencevolume 20pages94108 (2019) | Download Citation


The symptoms of Alzheimer disease reflect a loss of neural circuit integrity in the brain, but neurons do not work in isolation. Emerging evidence suggests that the intricate balance of interactions between neurons, astrocytes, microglia and vascular cells required for healthy brain function becomes perturbed during the disease, with early changes likely protecting neural circuits from damage, followed later by harmful effects when the balance cannot be restored. Moving beyond a neuronal focus to understand the complex cellular interactions in Alzheimer disease and how these change throughout the course of the disease may provide important insight into developing effective therapeutics.

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T.L.S.-J. and C.M.H. gratefully acknowledge funding from the UK Dementia Research Institute, the European Research Council (ALZSYN), Alzheimer’s Research UK, the Alzheimer’s Society, MND Scotland and the Euan MacDonald Centre for Motorneurone Disease Research. T.L.S.-J. is a member of the FENS Kavli Network of Excellence. The authors thank M. Tzioras for excellent critical review of the manuscript.

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Nature Reviews Neuroscience thanks O. Arancio and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. The University of Edinburgh Centre for Discovery Brain Sciences, UK Dementia Research Institute, Edinburgh, UK

    • Christopher M. Henstridge
    •  & Tara L. Spires-Jones
  2. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    • Bradley T. Hyman


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T.L.S.-J., B.T.H. and C.M.H. made substantial contributions to the discussion of content, writing, review and editing of the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Tara L. Spires-Jones.


Amyloid cascade hypothesis

Initially proposed in 1992, this hypothesis posits that the accumulation of amyloid-β (Aβ) is the initiating factor in Alzheimer disease pathogenesis, leading to the formation of amyloid plaques, neurofibrillary tangles, neuron loss and clinical dementia.

Innate immune system

Reactive response that utilizes chemical mediators to fight infection and clear foreign substances from the body by recruiting specialized immune cells. It can also activate a second wave of adaptive immune response by presenting antigens to adaptive immune cells.


The secretome includes all secretable factors released from a cell.

Oligomeric Aβ

Single molecules of Aβ are known as monomers. These monomers can aggregate to form oligomeric structures of two or more monomers, which can then accumulate into larger fibrillar forms of Aβ and deposit as the hallmark amyloid plaques.


Small releasable signalling proteins that often have immunomodulatory effects. These include chemokines, interleukins and interferons and they can be released by numerous immune cell types, endothelial cells and fibroblasts.

Homeostatic genes

Genes encoding a protein involved in a homeostatic mechanism within the cell.

Glymphatic system

Drainage pathway found in the vertebrate CNS that allows cerebrospinal fluid to enter the brain alongside penetrating arteries and facilitates the removal of interstitial fluid and waste products from the brain.

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