Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β

Since the identification of the apolipopmtein E (apoE) *epsilon 4 allele as a major genetic risk factor for late-onset Alzheimer's disease, significant efforts have been aimed at elucidating how apoE4 expression confers greater brain amyloid-beta (A beta) burden, earlier disease onset and worse clinical outcomes compared to apoE2 and apoE3. ApoE primarily functions as a lipid carrier to regulate cholesterol metabolism in circulation as well as in the brain. However, it has also been suggested to interact with hydrophobic A beta peptides to influence their processing in an isoform-dependent manner. Here, we review evidence from in vitro and in vivo studies extricating the effects of the three apoE isoforms, on different stages of the A beta processing pathway including synthesis, aggregation, deposition, clearance and degradation. ApoE4 consistently correlates with impaired A beta clearance, however data regarding A beta synthesis and aggregation are conflicting and likely reflect inconsistencies in experimental approaches across studies. We further discuss the physical and chemical properties of apoE that may explain the inherent differences in activity between the isoforms. The lipidation status and lipid transport function of apoE are intrinsically linked with its ability to interact with A beta. Traditionally, apoE-oriented therapeutic strategies for Alzheimer's disease have been proposed to non-specifically enhance or inhibit apoE activity. However, given the wide-ranging physiological functions of apoE in the brain and periphery, a more viable approach may be to specifically target and neutralise the pathological apoE4 isoform.

Automated summary

Research has shown a strong correlation between apoE4 and the risk of Alzheimer's disease, primarily due to increased brain Aβ burden, earlier disease onset, and worse clinical outcomes caused by apoE4. However, there is still debate on the effects of different apoE isoforms on various stages of the Aβ processing pathway, potentially reflecting inconsistencies in research methodologies.