Apolipoprotein E (APOE) is a 299 amino acid protein which can be induced by consuming foods rich in cholesterol. The APOE gene has three main alleles termed ε2-4, which are translated into the proteins ApoE2-4. Apolipoproteins play a role in the lipid metabolism of the blood. Raised plasma triglyceride concentrations are associated with ApoE2 and ApoE4 levels. People who have two copies of the ε4 allele have a 12-fold increased relative risk for developing Alzheimer’s disease. That said, ε4 status does not reliably predict the onset of Alzheimer’s.
In order to improve the predictive utility of ε4 status it is necessary to gain a better understanding of the underlying biology of the ε4 genotype. Pieter Jelle Visser of Vrije Universiteit Amsterdam, The Netherlands, and colleagues proteomically profiled cerebrospinal fluid (CSF) protein signatures to find APOE ε4 genotype-dependent associations with Alzheimer’s identified from 253 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The results were published in the journal Alzheimer’s Research & Therapy.
Overall, of the proteins with altered expression in the Alzhheimer’s condition, the majority (79%) were downregulation. Tau protein showed increased expression in all Alzheimer’s stages and was independent of ApoE4 status. However, the stage of Alzheimer’s disease determined the association with 90% of proteins in the CSF.
APOE ε4 carriers had both upregulated and downregulated proteins compared to the controls. Those without APOE ε4 and aggregated amyloid had a different proteomic profile. In those with APOE ε4, but no symptoms or amyloid markers, the Toll-like receptor signaling pathway was enriched.
Altered complement protein expression was associated with APOE ε4 carriers, however the role of complement in Alzheimer’s is still under investigation. Altered expression of proteins involved in glycolysis were also noted.
An independent replication cohort, although consistent overall, indicated that further replication with larger sample sizes may be required. The definition of Alzheimer’s disease used by this study was the presence of amyloid in the CSF, however 97% of the participants had no pathological data available, making the diagnosis of Alzheimer’s unclear.
In conclusion, we found CSF proteomic signatures that were associated with aggregated amyloid β and were dependent on APOE ε4 genotype and cognitive stage. An implication of our results is that [Alzheimer’s disease] subjects may require treatments tailored to APOE genotype and that clinical trials may need to consider APOE ε4 dependent endpoints in CSF, stated the authors.