# Interaction of sickle cell trait with human apolipoprotein E ε4: Impact on brain structure, brain lipidomics, neuroinflammation and cognitive deficit

> **NIH NIH R21** · UNIVERSITY OF CINCINNATI · 2024 · $445,500

## Abstract

ABSTRACT
With an increasing proportion of the population at older ages (i.e., the ‘graying of America’), there is a growing
prevalence of Alzheimer’s Disease and Related Dementias (ADRDs). By the year 2030, the number of “oldest”
Americans is expected to grow by 81% among non-Hispanic Whites (NHWs), 131% among African Americans,
328% among Hispanics and 285% among Asians/Pacific Islanders. Similarly, the direct and indirect cost of
AD/ADRD is estimated to be over $450 billion by the year 2030. The mortality related to dementias have also
increased by 71% from the year 2000 to 2013. Although the incidence and prevalence of dementia is expected
to increase significantly across all racial and ethnic groups. There is existing racial/ethnic disparity in the
incidence and prevalence of ADRDs. In general, the prevalence of all dementias is 2.5-fold higher among African
Americans compared to (NHWs), with recent prospective studies, showing that African Americans have a
significantly higher incidence of dementia and cognitive impairment even after adjusting for all relevant risk
factors. While the exact reasons for the existing racial disparity in AD/ADRD is not clearly known, one potential
reason, which is the focus of this proposal, is the sickle cell mutation (HbS), which is prevalent in individuals of
African ancestry but almost entirely absent among (NHWs). Our reasoning is based on two points (1) adjustment
for traditional dementia risk factors did not attenuate the observed disparity, and (2) despite the higher increase
in the proportion of “oldest” Americans among Asians/Pacific Islanders compared to NHWs (265% vs. 81%), the
incidence of dementia in both racial/ethnic groups is on par with each other, thus a higher proportion of oldest
individual is not likely the reason for the disparity. Given the high prevalence of the APOE ε4 risk allele (~37%)
among individuals of AAs and the fact that co-inheritance of any combination of the APOE ε4 risk allele (i.e. 2/4,
3/4 or 4/4) along with SCT is a common occurrence, as shown by our preliminary data, we hypothesize that the
combined presence of SCT and APOE ε4 ADRD risk allele, will lead to earlier onset and/or more severe cognitive
deficit, with accompanying increase in neuroinflammation and abnormal brain lipidomics profile compared to
controls. The findings from this proposal will provide insight into the mechanisms by which SCT modifies the
impact of APOE ε4 on ADRD risk, and thus contributes to differences in cognitive deficit and dementia observed
in our prior study among African Americans. This could allow us to address racial disparity in cognitive deficit.
Further, results from this study could provide a model system for the testing of therapies aimed specifically at
reducing racial/ethnic disparity in dementia therapy in people of African descent.

## Key facts

- **NIH application ID:** 10993275
- **Project number:** 1R21AG089843-01
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Hyacinth Idu Hyacinth
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $445,500
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993275

## Citation

> US National Institutes of Health, RePORTER application 10993275, Interaction of sickle cell trait with human apolipoprotein E ε4: Impact on brain structure, brain lipidomics, neuroinflammation and cognitive deficit (1R21AG089843-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10993275. Licensed CC0.

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