# How does D2-CD33 reduce Alzheimer's disease risk?

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2020 · $420,750

## Abstract

Elucidating the mechanism whereby genetics impact the risk of Alzheimer’s disease (AD) is a
critical barrier to progress in translating genetics to pharmacologic strategies. A polymorphism
near CD33 has been identified as an AD risk factor in multiple genome wide association studies,
including very recent, very large studies. CD33 is a member of the sialic acid-binding
immunoglobulin-type lectin (SIGLEC) family which is linked to regulation of innate immunity.
We and others have found that CD33 expression is restricted to microglia in the brain.
Moreover, the AD-protective allele acts to increase a CD33 isoform lacking exon 2 (D2-CD33) at
the expense of full-length CD33. Since exon 2 encodes the sialic acid ligand binding domain, we
interpreted the finding that loss of exon 2 was associated with decreased AD risk as meaning
that a decrease in functional CD33 and its associated immune suppression was AD-protective.
However, this interpretation needs to be reconsidered given our recent finding that a 4 bp CD33
genetic deletion, which abrogates CD33, is not associated with AD risk. In summary, we
currently propose a model wherein the D2-CD33 isoform represents a gain of function variant to
reduce AD risk because (i) a genetic polymorphism that reduces AD risk increases D2-CD33 at
the expense of “full-length” CD33 but (ii) a CD33 indel that essentially deletes cell surface CD33
does not affect AD risk. To test this model, we propose the following Specific Aims. Specific
Aim 1: Evaluate whether changes in CD33-related gene expression may compensate for CD33
deficiency. Specific Aim 2: Determine D2-CD33 subcellular localization under conditions of
physiologic D2-CD33 expression. Specific Aim 3: Compare CD33 and D2-CD33 interactomes.
Specific Aim 4: Compare impact of CD33 and D2-CD33 on cellular functions critical to
microglia. Successful completion of these studies will pinpoint D2-CD33 as the primary
pharmacologic target in this locus to reduce AD risk.

## Key facts

- **NIH application ID:** 10038417
- **Project number:** 1R21AG068370-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Steven Estus
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,750
- **Award type:** 1
- **Project period:** 2020-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10038417

## Citation

> US National Institutes of Health, RePORTER application 10038417, How does D2-CD33 reduce Alzheimer's disease risk? (1R21AG068370-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10038417. Licensed CC0.

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