# Protein Signatures of APOE2 and Cognitive Aging

> **NIH NIH R01** · TUFTS MEDICAL CENTER · 2020 · $654,306

## Abstract

Abstract
Apolipoprotein E is a class of proteins involved in lipid metabolism with functions determined by 
alleles of the gene APOE. The least common allele of this gene, called 𝑒2, emerged as a putative 
protective variant when Schachter et al. noted an increased frequency of 𝑒2 in French 
centenarians. Since then several studies have provided evidence that 𝑒2 has a beneficial neuroprotective 
effect and promotes longevity and healthy aging. The New England Centenarian Study (NECS) directed 
by Dr. Perls has enrolled ~400 𝑒2 carriers since 1994,
and in collaboration with the Longenity Study (LS) directed by Dr. Barzilai and other studies of 
centenarians produced strong evidence that 𝑒2promotes longevity. Despite multiple research 
efforts however the biological mechanisms associated with 𝑒2 are still unclear. We generated in 
collaboration with Novartis a proteomic dataset of ~5,000 proteins from sera of 226 NECS 
participants, ages 50 to 115 years, selected to be enriched
of 𝑒2 and we analyzed these data in the context of APOE genotypes. In our analysis, we 
discovered a preliminary set of proteins that correlate with APOE genotypes and predict different 
longitudinal patterns of cognitive decline. These preliminary data support the hypothesis that 
there are multiple plasma proteins associated with APOE genotypes that (i) can be used to predict 
cognitive decline or preservation better than APOE genotypes, and (ii) can inform us about 
potential mechanisms of action of APOE and suggest candidate interventions to prevent or delay 
neurodegenerative diseases and cognitive decline in aging. We propose to test this hypothesis in 
three ways: we will use in-depth proteomics to validate, characterize and expand the set of 
proteins that correlate with APOE genotypes in plasma of 50 carriers of different APOE genotypes. 
This analysis will likely discover additional protein biomarkers associated with APOE genotypes as 
well as post- translational modifications that could modify their molecular functions. We will then 
evaluate the effect of the expanded protein signature on aging and cognitive decline in 600 
centenarians, their offspring and controls from the NECS, and replicate findings with the LS. In a 
subset of these subjects, we will assay protein levels in a second blood sample collected few years 
apart to be able to examine how changes of the protein signature predict changes of cognitive 
functions. We also propose to augment these data with selected markers of inflammation and free 
fatty acids that are important factors in cognitive aging and conduct integrative analyses of the 
data collected in the various aims to model hypothetical mechanisms linking APOE genotypes to 
cognitive aging. In summary, we have assembled a competent, interdisciplinary team of investigators 
to thoroughly evaluate and characterize protein signatures of APOE genotypes that could become 
multipurpose, potent biomarkers of cognitive functions change and proba...

## Key facts

- **NIH application ID:** 9950970
- **Project number:** 7R01AG061844-03
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** THOMAS T PERLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $654,306
- **Award type:** 7
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950970

## Citation

> US National Institutes of Health, RePORTER application 9950970, Protein Signatures of APOE2 and Cognitive Aging (7R01AG061844-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9950970. Licensed CC0.

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