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Purpose of Review <p>Alzheimer’s disease (AD) is strongly influenced by genetic factors, with recent genome-wide association studies highlighting the MS4A gene cluster as a major locus beyond apolipoprotein E. This systematic review and bioinformatic analysis aimed to clarify the contribution of genes to AD pathogenesis.</p> Recent Findings <p>Twenty-nine studies (&gt; 43,000 AD cases and &gt; 66,000 controls) met the inclusion criteria. The most consistently associated variants were MS4A4A (rs1582763), MS4A6A (rs610932), MS4A4E (rs670139), and additional regulatory SNPs such as rs7232 and rs4938933. Most AD-associated variants in the MS4A region are intronic or intergenic regulatory SNPs acting as microglial expression quantitative trait loci, although coding variants (e.g., MS4A4A rs6591561, MS4A6A rs12453) also exist. Across multiple cohorts, MS4A4A and MS4A6A variants correlated with cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), microglial activation, lipid handling, and neuroinflammatory states.Bioinformatic enrichment using ClusterProfiler (FDR &lt; 0.05) revealed significant involvement of MS4A genes in cell-surface receptor signaling, plasma-membrane complexes, and the trans-Golgi network, supporting a mechanistic link to microglial immune regulation and amyloid precursor protein trafficking. </p> Summary <p>The MS4A gene cluster—particularly MS4A4A and MS4A6A—emerges as a key modulator of microglial biology and sTREM2 levels in late-onset AD. These variants influence microglial inflammatory phenotypes and lipid metabolism and converge on an MS4A–TREM2 regulatory axis. Plasma or CSF MS4A4A/MS4A6A levels and sTREM2 show promise as biomarkers of AD progression, although no validated clinical assay is yet available. The MS4A4A–TREM2 pathway represents a potential therapeutic target for modulating neuroinflammation in AD.</p>

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Unlocking the Genetic Code: A Systematic Review and Bioinformatic Analysis of the MS4A Gene Cluster’s Role in Alzheimer’s Disease

  • 期刊论文

  • 发表日期：

    2026年2月25日

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  • Narges Bazgir,
  • Matin Baghani,
  • Maryam Khanahmadi,
  • Nafiseh Sami,
  • Somayeh Niknazar,
  • Milad Rahimzadegan

摘要

Purpose of Review

Alzheimer’s disease (AD) is strongly influenced by genetic factors, with recent genome-wide association studies highlighting the MS4A gene cluster as a major locus beyond apolipoprotein E. This systematic review and bioinformatic analysis aimed to clarify the contribution of genes to AD pathogenesis.

Recent Findings

Twenty-nine studies (> 43,000 AD cases and > 66,000 controls) met the inclusion criteria. The most consistently associated variants were MS4A4A (rs1582763), MS4A6A (rs610932), MS4A4E (rs670139), and additional regulatory SNPs such as rs7232 and rs4938933. Most AD-associated variants in the MS4A region are intronic or intergenic regulatory SNPs acting as microglial expression quantitative trait loci, although coding variants (e.g., MS4A4A rs6591561, MS4A6A rs12453) also exist. Across multiple cohorts, MS4A4A and MS4A6A variants correlated with cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), microglial activation, lipid handling, and neuroinflammatory states.Bioinformatic enrichment using ClusterProfiler (FDR < 0.05) revealed significant involvement of MS4A genes in cell-surface receptor signaling, plasma-membrane complexes, and the trans-Golgi network, supporting a mechanistic link to microglial immune regulation and amyloid precursor protein trafficking.

Summary

The MS4A gene cluster—particularly MS4A4A and MS4A6A—emerges as a key modulator of microglial biology and sTREM2 levels in late-onset AD. These variants influence microglial inflammatory phenotypes and lipid metabolism and converge on an MS4A–TREM2 regulatory axis. Plasma or CSF MS4A4A/MS4A6A levels and sTREM2 show promise as biomarkers of AD progression, although no validated clinical assay is yet available. The MS4A4A–TREM2 pathway represents a potential therapeutic target for modulating neuroinflammation in AD.