# Harnessing Single Cell Epigenome-wide profiling of Myeloid cells to Compare and Contrast Alzheimer's from HIV-Associated Cognitive Dysfunction

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $819,055

## Abstract

Project Summary
The CDC estimated that one-quarter of Americans living with HIV were over the age of 55 in 2012. By next
year, these individuals will be over age 60, entering into the age demographic where Alzheimer's disease (AD)
becomes a distinct differential for clinicians. Because up to one-half of people living with HIV experience
cognitive impairment from HIV or related factors, the likelihood for masking and thus delaying the diagnosis of
early AD is substantial. Differentiating HIV-associated Neurocognitive Disorder (HAND) from the Mild Cognitive
Impairment stage of AD (MCI-AD) is one of the most pressing issues in geriatric neuroHIV. Current HAND
nosology does not provide guidance on this issue. Published work suggests the likelihood for distinct
phenotypes that would facilitate diagnostic sorting with commonly available inputs from neuropsychological
testing and structural imaging, but these may not be sufficient. Many studies highlight the importance of
myeloid cells (monocytes, macrophages and microglia) in the pathogenesis of both HAND and AD. In this
application we propose to harness the power of epigenetics utilizing cell type specific signatures and cutting-
edge single cell technologies to define distinguishing and overlapping immune biomarkers of HAND from the
MCI-AD in individuals over 60 years of age. This application will test the hypothesis that a rare population of
circulating monocytes in blood defined by an indelible epigenetic profile related to the CNS are present in
HAND compared to age-matched cognitively normal HIV+ individuals over age 60 on suppressive anti-
retroviral therapy. We further posit that comprehensively defining this HAND-related monocyte cell type will aid
in distinguishing HAND from individuals with MCI-AD while also defining fundamental neuropathogenic
mechanisms of each disease. The specific aims are Aim 1: To examine monocyte epigenetic phenotypes
in individuals over 60 years with early MCI-AD compared to HAND and, separately, cognitively normal
age-matched HIV+ individuals on suppressive ART. Aim 2 To utilize single cell resolution technology
to interrogate unique monocyte subpopulation phenotypes that can be used to compare and contrast
with MCI-AD and HAND. Aim 3: To validate MCI-AD and HAND related signatures in primary monocytes
and define functional consequences of site-specific methylation events. Two major outcomes are
expected from the knowledge gained by this proposal: (1) to reveal biological pathways to understand the
pathogenesis of HAND and MCI-AD. and 2) address the challenges of distinguishing HAND from Mild
Cognitive Impairment due to AD in geriatric neuroHIV.

## Key facts

- **NIH application ID:** 10125071
- **Project number:** 5R01AG063846-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Lishomwa C Ndhlovu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $819,055
- **Award type:** 5
- **Project period:** 2020-03-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125071

## Citation

> US National Institutes of Health, RePORTER application 10125071, Harnessing Single Cell Epigenome-wide profiling of Myeloid cells to Compare and Contrast Alzheimer's from HIV-Associated Cognitive Dysfunction (5R01AG063846-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10125071. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*