APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease

Makis Tzioras, Caitlin Davies, Anastasia Newman, Rosemary Jackson, Tara Spires-Jones

Research output: Contribution to journalArticlepeer-review


Despite more than a century of research, the aetiology of sporadic Alzheimer's disease (AD) remains unclear and finding disease modifying treatments for AD presents one of the biggest medical challenges of our time. AD pathology is characterised by deposits of aggregated amyloid beta (Aβ) in amyloid plaques and aggregated tau in neurofibrillary tangles. These aggregates begin in distinct brain regions and spread throughout the brain in stereotypical patterns. Neurodegeneration, comprising loss of synapses and neurons, occurs in brain regions with high tangle pathology, and an inflammatory response of glial cells appears in brain regions with pathological aggregates. Inheriting an apolipoprotein E ε4 (APOE4) allele strongly increases the risk of developing AD for reasons that are not yet entirely clear. Substantial amounts of evidence support a role for APOE in modulating the aggregation and clearance of Aβ, and data have been accumulating recently implicating APOE4 in exacerbating neurodegeneration, tau pathology and inflammation. We hypothesise that APOE4 influences all the pathological hallmarks of AD and may sit at the interface between neurodegeneration, inflammation and the spread of pathologies through the brain. Here we conducted a systematic search of the literature and review evidence supporting a role for APOE4 in neurodegeneration and inflammation. While there is no direct evidence yet for APOE4 influencing the spread of pathology, we postulate that this may be found in future based on the literature reviewed here. In conclusion, this review highlights the importance of understanding the role of APOE in multiple important pathological mechanisms in AD. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalNeuropathology and Applied Neurobiology
Early online date5 Nov 2018
Publication statusE-pub ahead of print - 5 Nov 2018


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