Abstract
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 characterized 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 hypothesize 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.
Highlights
The greatest genetic risk factor for sporadic Alzheimer’s disease (AD) is a polymorphism in the apolipoprotein E (APOE) gene
Imaging studies in AD populations repeatedly demonstrated possession of an apolipoprotein E ε4 (APOE4) allele to be associated with more extensive atrophy in disease-specific brain regions such as the medial temporal lobe [3,11,12,13,14,15,16,17,18,19,20,21,22,23], this was not universal [24,25]
This is unsurprising when considering that brain structures located here have clinical correlates to well-defined AD symptoms, and that APOE4 carriers are at increased risk of developing these symptoms in the form of AD
Summary
The greatest genetic risk factor for sporadic AD is a polymorphism in the apolipoprotein E (APOE) gene. The inheritance of two copies of APOE4 increases the chance of developing AD by 12 times compared to the risk of a person with two copies of APOE3. Homozygous APOE4 carriers who develop AD have a lower average age of clinical onset of 68 years of age compared to an average age of onset of 84 for an individual with two copies of APOE3. One copy of APOE4 increases the chance of AD by 3 times and lowers the average age of onset to 76 years of age [1]. Mentioned in association with AD most frequently, APOE has been linked to Parkinson’s Disease [2], Frontotemporal dementia [3] and other neurological diseases (reviewed in [4]) as well as linked to lower cognition in non-demented aged individuals [5]. The pathways by which APOE impacts the development of AD have been widely studied both in vitro and in vivo the exact mechanisms have yet to be uncovered
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