MS4A4E encodes a membrane-spanning protein with four transmembrane domains and is primarily recognized for its role in Alzheimer's disease (AD) susceptibility. As a member of the MS4A gene cluster, MS4A4E was identified as a novel AD risk locus through genome-wide association studies 1. The gene demonstrates functional relevance in immune response pathways; transcriptomic analysis shows MS4A4E expression is downregulated during monocyte-to-macrophage differentiation, clustering with genes associated with cell cycle and DNA replication processes 2. MS4A4E exhibits age-dependent genetic effects on AD risk, with stronger associations in younger-onset AD (60-79 years) 3, and shows genetic interactions with CLU and CD33 variants that significantly modulate AD susceptibility independent of APOE ε4 status 4. The CLU-MS4A4E interaction shows a combined odds ratio of 2.45 and population attributable fraction of 8%, representing one of the strongest non-APOE/APP/TREM2 associations in AD 4. Additionally, MS4A4E expression shows age-dependent variance changes in brain tissue, suggesting differential regulation across the lifespan 5. Recent evidence implicates MS4A4E in early-onset AD through shared genetic architecture with lipid metabolism pathways 6, and associations have been validated across diverse populations including Han Chinese 7.