Abstract
The discovery of treatments to prevent or delay dementia and Alzheimer's disease is a priority. The gene APOE is associated with cognitive change and late‐onset Alzheimer's disease, and epidemiological studies have provided strong evidence that the e 2 allele of APOE has a neuroprotective effect, it is associated with increased longevity and an extended healthy lifespan in centenarians. In this study, we correlated APOE genotype data of 222 participants of the New England Centenarian Study, including 75 centenarians, 82 centenarian offspring, and 65 controls, comprising 55 carriers of APOE e 2, with aptamer‐based serum proteomics (SomaLogic technology) of 4,785 human proteins corresponding to 4,137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes and replicated the signature in three independent studies. We also show that the protein signature tracks with gene expression profiles in brains of late‐onset Alzheimer's disease versus healthy controls. Finally, we show that seven of these proteins correlate with cognitive function patterns in longitudinally collected data. This analysis in particular suggests that Baculoviral IAP repeat containing two (BIRC2) is a novel biomarker of neuroprotection that associates with the neuroprotective allele of APOE. Therefore, targeting APOE e 2 molecularly may preserve cognitive function.
Highlights
The prevalence of late‐onset Alzheimer's disease (LOAD), dementia, and cognitive impairment is growing with the aging population, and reliable plasma/serum biomarkers that can be used for pre‐clinical diagnosis, monitoring and prediction of cognitive decline, onset of cognitive impairment, and for suggesting therapeutic targets are lacking (Cheng et al, 2018; Xia, Jiang, McDermott, & Han, 2018)
Recent publications have shown the richness of the proteome of human plasma and serum and the fact that proteins expressed in serum can be helpful to detect potential regulatory mechanisms (Emilsson et al, 2018), as well as to discover accessible diagnostic and prognostic biomarkers (Hathout, 2015)
We combined access to the largest plex aptamer‐based proteomic platform available, and a relatively large number of serum samples from a unique population enriched for carriers of e2, healthy agers and extreme survivors to discover a novel protein signature of the APOE genotypes
Summary
The prevalence of late‐onset Alzheimer's disease (LOAD), dementia, and cognitive impairment is growing with the aging population, and reliable plasma/serum biomarkers that can be used for pre‐clinical diagnosis, monitoring and prediction of cognitive decline, onset of cognitive impairment, and for suggesting therapeutic targets are lacking (Cheng et al, 2018; Xia, Jiang, McDermott, & Han, 2018). One strategy to understand the paths linking APOE alleles to pheno‐ types is to examine their biological products, starting, for example, from the list of genes that are in cis and in trans with APOE alleles. The challenge of these analyses is the tissue specificity of the results, the relative rarity of carriers of the e2 allele in the population, and the fact that relevant tissues like brain are not accessible. We showed that some of the proteins in the signature correlate with pat‐ terns of cognitive function
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