The Immune Thread Tying MS, Alzheimer’s, Parkinson’s, and Huntington’s Together

A meta-analysis across public brain transcriptomes (microarray + RNA-seq) found a single, shared immune gene co-expression module—rich in microglia, monocyte, and macrophage signatures—linked not just to multiple sclerosis (MS) but also to three neurodegenerative diseases: Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s (HD). That module (ModArray_04 in microarrays; ModRNAseq_06 in RNA-seq) lights up immune and inflammatory biology (neutrophil activation, cytokine and Toll-like receptor signaling) and points to actionable targets and repurposing opportunities.

Why this matters
Neurodegeneration is often framed as neuron-centric (plaques, tangles, dopaminergic loss, huntingtin toxicity). MS, in contrast, is the textbook immune-mediated brain disease. This study bridges those worlds: the same immune network that’s obvious in MS is also consistently engaged in AD, PD, and HD—even after careful normalization to strip away age and study effects. That’s a strong nudge toward immunomodulation as a unifying therapeutic angle.

What the authors did (in plain English)
Data: Public human brain datasets across AD, PD, HD, MS and controls, spanning both microarrays and RNA-seq. The analysis treated platforms in parallel to avoid platform bias.

Normalization & batch correction: A Surrogate Variable Analysis + linear model (SVA+LM) pipeline removed confounders (study/batch, sex, age, tissue) before any network work—validated by density plots, PCA, and cross-study correlations (clear “before vs after” improvements).

Networks: Built WGCNA co-expression modules separately for microarray (23 modules) and RNA-seq (29 modules), then checked which modules associate with each disease and which are preserved across platforms.

Cell-type markers: Derived consensus marker sets for neurons, astrocytes, oligodendrocyte lineages, endothelial cells, and immune cells (microglia, monocytes, macrophages) from differential expression meta-analysis (limma, edgeR, and a simple mean-comparison)—then enriched those markers into disease modules.

The headline result
Across platforms, one immune-heavy module shows up consistently with all four diseases:

Microarray: ModArray_04 (335 genes)

RNA-seq: ModRNAseq_06 (1,586 genes)

Gene overlap between the two: 149 genes (p ≈ 2.1×10⁻⁸⁴)—that’s not random.

This module is enriched for microglia, monocyte, and macrophage marker genes—a trifecta seen only here among many disease-associated modules. In contrast, neurons, astrocytes, oligodendrocytes, and endothelial cells each map to separate modules. That pattern argues that innate immune cell types co-travel in a shared regulatory network, distinct from classical brain cell networks.

What biology is inside the shared immune module?
Gene Ontology enrichments read like an immunology syllabus:

Neutrophil activation & degranulation

Cytokine-mediated signaling

TLR signaling (including MyD88-dependent)

Interferon-γ responses
Positive regulation of T-cell activation/proliferation

Protein phosphorylation / intracellular signal transduction

The largest single term in both platforms was “neutrophil activation involved in immune response.”

Numbers that help anchor the story
Modules detected: 23 (arrays), 29 (RNA-seq). Largest modules: 2,141 and 3,240 genes; smallest: 29 and 105, respectively.

Disease associations: 22 microarray and 27 RNA-seq modules significantly linked to AD/PD/HD/MS; preservation between platforms was widespread.

Cell marker sets (consensus DEG approach): e.g., ~592 macrophage, 344 microglia, 863 monocyte markers (at FC>1.25, p < 0.05 in ≥2 methods).

Important caveats (and how the authors handled them)
PD tissue mismatch: PD RNA-seq samples came from cortex, while microarray PD samples were from substantia nigra—some RNA-seq PD associations fell below significance. Even so, cell-type enrichment agreed between platforms where PD modules were significant.

Species source for markers vs disease modules: Cell-type marker derivation used mouse datasets, while disease modules are human—an unavoidable translational step, openly noted.

Therapeutic takeaways
Network medicine, not single genes: The findings support targeting immune pathways and modules rather than isolated markers. Past AD trials with general anti-inflammatories underperformed, while pathway-specific inhibitors fared better—consistent with the idea that precision within the immune system matters.

Drug repurposing potential: A shared immune module across AD, PD, HD, and MS is an invitation to repurpose immunomodulators. The paper highlights dimethyl fumarate (approved in MS, macrophage-modulating) being evaluated/used in HD as a proof-of-concept example.

How to read the cell-type mapping at a glance
Neurons → ModArray_03 / ModRNAseq_14 (neuron-rich, disease-associated)

Astrocytes → ModArray_10/20 / ModRNAseq_07

Oligodendrocytes (myelinated) → ModArray_06 / ModRNAseq_08

Endothelial → ModArray_14 / ModRNAseq_18

Innate immune (microglia, monocytes, macrophages) → ModArray_04 / ModRNAseq_06 (the shared, cross-disease immune module)

What’s next?
Deconvolution & single-cell follow-ups: Validate whether the shared immune module reflects cellular composition shifts, state changes within microglia/monocytes/macrophages, or both; single-cell/ nuclei RNA-seq + chromatin profiling would help. (The current study already took steps to separate cell signatures from bulk networks via marker enrichment.)

Causality & directionality: Is the immune module driving degeneration or responding to it? Longitudinal data and perturbation studies are the next pieces.

Stratified trials: Given the heterogeneity across diseases and brain regions, consider module-guided patient stratification to match immunotherapies to the patients whose immune network is truly engaged.

Bottom line
Despite different clinical labels and histopathology, AD, PD, HD, and MS share an immune-centric gene network in the brain. If you’re thinking about targets, think modules and pathways—especially those connecting microglia, monocytes, and macrophages—and consider repurposing where the network biology aligns.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Mukherjee, S. (2021). Immune gene network of neurological diseases: Multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Heliyon, 7(12). x"