# The role of peripheral myeloid cells in Alzheimers disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $825,123

## Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive
decline and dementia. Recent genome scans have identified over twenty novel AD susceptibility loci, and several
of these loci implicate the immune system. Our recent gene expression analyses of data from healthy young
individuals have implicated 12 AD susceptibility genes in myeloid cell function, whose expression, relative to each
risk allele, is altered in the primary monocytes. We have also recently identified AD risk-increasing alleles of the
myeloid cell surface receptor CD33 that are associated with diminished Aβ uptake by human monocytes.
Furthermore, AD GWAS signals, as well as the most strongly validated coding variants associated with AD (in
APOE, TREM2 and ABCA7), coalesce around genes that are necessary for efficient phagocytic clearance of
cellular debris by myeloid cells. Therefore, these loci represent excellent candidates as the first step in the cascade
of molecular events that link genetic risk factors to the altered innate immune function that contributes to AD
pathology. Indeed there is conflicting evidence as to the relative importance in AD pathogenesis of peripheral
myeloid cells that subsequently enter the brain versus tissue resident myeloid cells such as microglia. Because of
their shared ontology regulation of expression of many myeloid specific genes is likely to be shared between
monocytes and microglia. Given the ease of access to blood monocytes throughout the disease process, compared
to microglia that are only accessible at autopsy we propose to explore the functional consequences of commonly-
occurring genetic variation on the transcriptome in peripheral monocytes from AD patients. Our central hypothesis
is that peripheral monocyte-derived cells, such as macrophages and monocytes will manifest changes in gene
expression of these AD susceptibility genes and other genes in the same molecular pathways that reflect the
stages of AD pathophysiology. To test this hypothesis, we will characterize the transcriptome/methylome profiles
from peripheral monocytes of 200 AD cases and 200 age-matched controls. This will be followed up with profiling of
monocytes stimulated with anti- (myelin) and pro-inflammatory (LPS and Aβ) stimuli. Through innovative
computational approaches, we will integrate various datasets from monocytes in order to identify causal drivers and
molecular networks underlying AD pathogenesis such as Aβ clearance and neuroinflammation. We will also
incorporate data from over 500 AD brains to assess if the monocyte-specific transcriptional networks recapitulate
changes seen in the AD brains. Finally, we will perform highly multiplexed mass cytometry-based immune
phenotype profiling to investigate the activation state and phagocytic capacity of monocytes. We will validate our
most promising candidate genes from the functional studies in human microglia using immunohistochemistry. The
proposed research i...

## Key facts

- **NIH application ID:** 9895593
- **Project number:** 5R01AG054005-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Towfique Raj
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $825,123
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895593

## Citation

> US National Institutes of Health, RePORTER application 9895593, The role of peripheral myeloid cells in Alzheimers disease (5R01AG054005-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9895593. Licensed CC0.

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