The MUC6/AP2A2 locus and its relevance to Alzheimer's disease: A review

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11 Scopus citations


We recently reported evidence of Alzheimer's disease (AD)- linked genetic variation within the mucin 6 (MUC6) gene on chromosome 11p, nearby the adaptor-related protein complex 2 subunit alpha 2 (AP2A2) gene. This locus has interesting features related to human genomics and clinical research. MUC6 gene variants have been reported to potentially influence viral - including herpesvirus - immunity and the gut microbiome. Within the MUC6 gene is a unique variable number of tandem repeat (VNTR) region. We discovered an association between MUC6 VNTR repeat expansion and AD pathologic severity, particularly tau proteinopathy. Here, we review the relevant literature. The AD-linked VNTR polymorphism may also influence AP2A2 gene expression. AP2A2 encodes a polypeptide component of the adaptor protein complex, AP-2, which is involved in clathrin-coated vesicle function and was previously implicated in AD pathogenesis. To provide background information, we describe some key knowledge gaps in AD genetics research. The "missing/hidden heritability problem"of AD is highlighted. Extensive portions of the human genome, including the MUC6 VNTR, have not been thoroughly evaluated due to limitations of existing high-throughput sequencing technology. We present and discuss additional data, along with cautionary considerations, relevant to the hypothesis that MUC6 repeat expansion influences AD pathogenesis.

Original languageEnglish
Pages (from-to)568-584
Number of pages17
JournalJournal of Neuropathology and Experimental Neurology
Issue number6
StatePublished - 2021

Bibliographical note

Funding Information:
From the Sanders-Brown Center on Aging (PTN, DWF, YK); Department of Pathology (PTN); and Department of Biostatistics (DWF, YK), Univer-sity of Kentucky, Lexington, Kentucky Send correspondence to: Peter T. Nelson, MD, PhD, Rm 311 Sanders-Brown Center on Aging, 800 S. Limestone Avenue, Lexington, KY 40536; E-mail: Funding included grants P30 AG028383, R01 AG057187, R01 AG042475, R56 AG057191, and U01 AG016976 from the National Institute on Aging/National Institutes of Health (NIH). The Genotype-Tissue Expres-sion (GTEx) project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. We are deeply grateful to all of the study participants, clini-cal workers, and researchers who helped make this article possible. See Supplementary Data for additional acknowledgments.

Publisher Copyright:
© 2020 American Association of Neuropathologists, Inc.


  • APOE
  • Alzheimer's Disease Sequencing Project (ADSP)
  • Amyloid
  • Copy number variation (CNV)
  • Endocytosis
  • Genome-wide association study (GWAS)
  • Whole-exome sequencing (WES)

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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