All of Us – More Inclusive Research for Better Treatment
The NIH is leading an effort – All of Us – to correct long-standing disparities in biomedical research resulting in treatments best serving white males. ISB’s Hood and Hadlock Labs, with NIH support, are analyzing All of Us data from 800,000 enrollees, 80% from underrepresented populations, on the effect of genetic variants – which may vary based on sex, race and ethnicity – on disease risk.
Image credit: NIH All of Us from their sharable resources archive.
A certain form of the gene known as apolipoprotein E (APOE), APOE4, is strongly linked to risk of developing Alzheimer’s disease, while another APOE variant, APOE2, is correlated with longer lifespans and is also protective against Alzheimer’s. The APOE protein transports cholesterol in the brain and also appears to help clear the beta-amyloid plaque buildup associated with Alzheimer’s and other forms of brain aging. How the variants of the APOE gene exert their effect on longevity and Alzheimer’s risk remains unclear. ISB’s Noa Rappaport, PhD, is exploring how these different variants of APOE affect their carriers throughout their lifespan and how the variants might influence biological aging and metabolism.
- Funded by the National Institute on Aging
- Led by Noa Rappaport, PhD
- Key collaborators:
- Dylan Ellis, Kengo Watanabe, PhD, and Cory Funk, PhD, ISB
- Priyanka Baloni, PhD, Purdue University
Exploring the role of a key protein in longevity and Alzheimer’s disease
Due to APOE’s role in lipid metabolism through its interactions with cholesterol, Rappaport and her team wanted to apply a systems biology lens to metabolic differences in people carrying the different variants of the gene. Metabolic processes have also been implicated in Alzheimer’s disease.
In initial studies, they used data from nearly 4,000 people who were part of either the TwinsUK cohort, a registry of adult twins that collects biological samples and data on a variety of diseases, or Arivale, a former ISB spinout company that analyzed customers’ genetic, protein and metabolic information in relation to their health.
They looked at a suite of nearly 900 different metabolites and tested whether their levels showed any correlation to an individual’s APOE gene status, their chronological age, their sex, or a measure known as biological age, which may be different from chronological age and has been shown to associate with health state in previous studies. They also looked at how APOE variants affect system-wide interactions among different kinds of molecules, including metabolites, proteins, and gut microbiome species.
In that study, they found several classes of metabolites that seem to differ by APOE status, especially those known as diacylglycerols. Interestingly, they found that both APOE2 and APOE4 had similar associations with blood metabolites in healthy, younger individuals. Additionally, APOE2, the variant that is associated with longevity, affected the interactions in a similar way as did biological oldness.
Rappaport and her colleagues are now using data from the National Institutes of Health’s All of Us research program, which has enrolled more than half a million study participants. The All of Us dataset includes detailed clinical information as well as participants’ genome sequences. The researchers want to use the larger and more ethnically diverse dataset to study how APOE variants intersect with several health and disease states, including cholesterol levels and heart disease, throughout adulthood.
Citations
- Ellis D, Watanabe K, Wilmanski T, Lustgarten MS, Ardisson Korat AV, Hadlock JJ, Fiehn O, Sebastiani P, Price ND, Hood L, Magis AT, Evans SJ, Pflieger L, Lovejoy JC, Gibbons SM, Funk CC, Baloni P, Rappaport N. APOE Genotype and Biological Age Impact Inter-Omic Associations Related to Bioenergetics. bioRxiv 2024. doi: https://doi.org/10.1101/2024.10.17.618322
Contact Dr. Noa Rappaport
Principal Scientist
ISB