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Alpha-2 macroglobulin is genetically associated with Alzheimer disease

D Blacker1, M A Wilcox, N M Laird

  • 1Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, USA.

Nature Genetics
|August 11, 1998
PubMed

Insights

A deletion in the Alpha-2-macroglobulin (A2M) gene increases Alzheimer disease risk. This genetic link suggests A2M may play a role in Alzheimer disease development, similar to APOE-epsilon4.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Alpha-2-macroglobulin (alpha-2M) is a serum protease inhibitor involved in amyloid-beta clearance.
  • Alzheimer disease (AD) is characterized by beta-amyloid deposits, a key component alpha-2M can degrade.

Purpose of the Study:

  • To investigate the association between a specific A2M gene deletion (A2M-2) and Alzheimer disease risk.
  • To compare the risk conferred by A2M-2 with the well-established APOE-epsilon4 allele.

Main Methods:

  • Analysis of a deletion in the A2M gene at the 5' splice site of exon II.
  • Statistical analysis including Mantel-Haenzel odds ratio and sibship disequilibrium test (SDT).
  • Comparison with APOE-epsilon4 allele data from the same sample.

Main Results:

  • Inheritance of the A2M-2 deletion significantly increases AD risk (OR=3.56, P=0.001).
  • SDT confirmed a significant association between A2M and AD (P=0.00009).
  • A2M-2 did not influence age of onset, unlike APOE-epsilon4.

Conclusions:

  • The A2M gene deletion is a risk factor for Alzheimer disease.
  • A2M, LRP1, APOE, and APP genes linked to AD suggest a common neuropathogenic pathway.
  • A2M may contribute to AD pathogenesis through its role in amyloid-beta processing.

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