African Americans carrying a variant in a cholesterol-processing gene have double the risk for Alzheimer’s than non-carriers. This gene, for a membrane transporter protein called ABCA7, is the greatest difference between African American and Caucasian Alzheimer’s risk to emerge from the largest genomewide association study (GWAS) for AD performed in African Americans to date. The study appears April 10 in the Journal of the American Medical Association. In African Americans, ABCA7 variation is the strongest genetic risk factor for AD outside of the ApoE4 allele. Other than that, the genes involved in African American AD risk paralleled those in whites, reported the study authors representing the Alzheimer's Disease Genetics Consortium.

Led by senior author Richard Mayeux at Columbia University in New York City, the researchers examined single-nucleotide polymorphisms from nearly 2,000 people with late-onset Alzheimer’s, and almost 4,000 control participants. The group collected all the data it could get from African Americans seen at more than 20 study centers, said first author Christiane Reitz, also at Columbia.

While many of the previously reported GWAS data come from people of European and European American ancestry, Reitz noted that it is important to investigate whether those genetic findings extend to people beyond that white slice of humanity. A GWAS in Hispanics is ongoing.

Several of the genes the current study picked out in African Americans matched those found in GWAS with white people. ApoE4 was the strongest risk factor; a single copy more than doubled risk of Alzheimer’s with an odds ratio of 2.31 in this report. “Replicating an association for the same alleles in different ethnic groups strengthens the case for these variants being important in increasing disease susceptibility,” commented Robert Nussbaum of the University of California, San Francisco, in an editorial accompanying the publication.

After ApoE, ABCA7 was second on the hit list. ABCA7 variants had been reported to increase risk in white people, but ABCA7 was in the middle of the pack among genes linked to AD, most of which boost risk by an average of 10-20 percent, Reitz said (Hollingworth et al., 2011). ABCA7 currently ranks fourth on the AlzGene Top 10. In the new study’s African American population, an ABCA7 variant increased one’s chances of AD by almost double, with an odds ratio of 1.79.

This kind of race-based difference is not uncommon, Reitz noted. She suspects that the ABCA7 polymorphisms found in Caucasians point to specific functional mutations different from those carried by African Americans, but the researchers have not yet sequenced the gene to check. It is also possible that the genetic background of each race, as well as environmental factors, conspire with ABCA7 variants to produce a higher risk in African American carriers than in whites.

It is too early to think about genetic testing or ABCA7-based therapies, Reitz said. For now, researchers have to confirm the disease association in an independent population and study the biological function of the gene. That is no small task. ABCA7’s functions fit with the AD literature in that lipid dysregulation and cardiovascular disease are known risk factors (Breteler, 2000; Shepardson et al., 2011). ABCA7 encodes an ATP-binding transporter that participates in lipoprotein biogenesis, and secretion of phospholipids and cholesterol (Tanaka et al., 2011). It also influences the transport of amyloid precursor protein across the plasma membrane (Chan et al., 2008). “There are multiple ways in which ABCA might affect risk of late-onset Alzheimer's disease,” the study authors wrote.—Amber Dance.

References:
Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS, Valladares O, Lin CJ, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldswin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hendrie H, Hall KS, Goate AM, Byrd GS, Kukull WA, Foroud TM, Haines JL, Farrer LA, Pericak-Vance MA, Schellenberg GD, Mayeux R, for the Alzheimer Disease Genetics Consortium. Variants in the ATP-binding cassette transporter (ABCA), apolipoprotein E4, and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013 Apr 10;309(14):1483-92. Abstract

Nussbaum RL. Genome-wide association studies, Alzheimer disease, and understudied poulations. JAMA. 2013 Apr 10;309(14):1527-8. Abstract

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References

Paper Citations

  1. . Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. PubMed.
  2. . Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging. 2000 Mar-Apr;21(2):153-60. PubMed.
  3. . Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Arch Neurol. 2011 Oct;68(10):1239-44. PubMed.
  4. . Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system. J Atheroscler Thromb. 2011;18(4):274-81. PubMed.
  5. . ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem. 2008 Jul;106(2):793-804. PubMed.
  6. . Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013 Apr 10;309(14):1483-92. PubMed.
  7. . Genome-wide association studies, Alzheimer disease, and understudied populations. JAMA. 2013 Apr 10;309(14):1527-8. PubMed.

External Citations

  1. Alzheimer's Disease Genetics Consortium
  2. ApoE4
  3. ABCA7
  4. AlzGene

Further Reading

Papers

  1. . Genome-wide association studies, Alzheimer disease, and understudied populations. JAMA. 2013 Apr 10;309(14):1527-8. PubMed.
  2. . Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013 Apr 10;309(14):1483-92. PubMed.
  3. . Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population. Alzheimers Dement. 2012 Dec 8; PubMed.
  4. . Genetics of Alzheimer's disease. Arch Med Res. 2012 Nov;43(8):622-31. PubMed.
  5. . Association of the CR1 polymorphism with late-onset Alzheimer's disease in Chinese Han populations: a meta-analysis. Neurosci Lett. 2012 Oct 3;527(1):46-9. PubMed.
  6. . Association of GWAS Top Hits With Late-onset Alzheimer Disease in Korean Population. Alzheimer Dis Assoc Disord. 2012 Sep 11; PubMed.
  7. . Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS). Neurobiol Aging. 2012 Aug;33(8):1849.e5-1849.e18. PubMed.
  8. . For Alzheimer disease GWAS, pulling needles from the haystack is just the first step. Neurology. 2012 Jul 17;79(3):204-5. PubMed.

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  7. Barcelona: What Lies Beyond Genomewide Association Studies?
  8. LOADing Up—Largest GWAS to Date Confirms Two, Adds Two Risk Genes
  9. Paper Alert: GWAS Hits Clusterin, CR1, PICALM Formally Published

Primary Papers

  1. . Genome-wide association studies, Alzheimer disease, and understudied populations. JAMA. 2013 Apr 10;309(14):1527-8. PubMed.
  2. . Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013 Apr 10;309(14):1483-92. PubMed.