A serum protein signature of APOE genotypes in centenarians

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.

Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

“…Of the cognitive score traits, Processing Speed and General Fluid Cognitive Ability scores were associated with the highest numbers of protein markers (268 and 127, respectively; Supplementary Table 14). Six of the 11 APOE associations replicated previous SOMAmer protein findings 10 , and the five novel relationships were for NEFL, ING4, MENT, PAF and TMCC3. The strongest association for APOE was observed with levels of LRRN1 (Beta = 0.57, SE = 0.03, FDR P = 1.73x10 -104 ); a selection of associations for APOE are presented in Fig.…”

“…Epigenetic modifications account for inter-individual variability in circulating protein levels [1][2][3] and have been linked to a range of neurological outcomes [4][5][6] and neurodegenerative conditions such as Alzheimer's disease 7 . Proteome-wide characterisation of blood protein signatures has also been facilitated at large-scale by SOMAscan ® protein measurements, with studies that have begun to map plasma protein signatures of cognitive decline and dementia risk [8][9][10] . There is, however, a need to further integrate omics datasets at large-scale to characterise and predict disposition to complex disease.…”

Studying the Interplay Between Apolipoprotein E and Education on Cognitive Decline in Centenarians Using Bayesian Beta Regression

“…For example, we identified a cluster of participants in the Long Life Family study who have slower decline of processing speed and attention and are genetically enriched for the e2 allele (Sebastiani et al 2020). These results suggest that targeting e2 gene products could lead to important therapeutics (Sebastiani, Monti, et al 2019). The interaction between education and the e2 allele is also consistent with the fact that more years of education is associated with better cognitive function in later life (Alley et al, 2007; Wilson et al, 2009).…”

Studying the Interplay Between Apolipoprotein E and Education on Cognitive Decline in Centenarians Using Bayesian Beta Regression

“…Our studies also found that carriers of e2 with low education can delay their onset of moderate cognitive impairment. These results suggest that targeting e2 gene products could lead to important therapeutics for the preservation of cognitive function (Sebastiani et al, 2019b). Interestingly, the persistence of the e4 allele in the population has been linked to a survival advantage at a young age and treatments that target the effect of APOE alleles at an older age will need to consider the pleiotropic effect of this gene (Belloy et al, 2019).…”