African Americans have about double the risk of dementia as their non-Hispanic white peers. How much of this is genetics, how much is environment? With the biggest genome-wide association study on African Americans to date, researchers led by Brian Kunkle at the University of Miami in Florida and Christiane Reitz at Columbia University in New York inched closer to answering this question. At just more than 8,000 participants, the study was still small by GWAS standards. It identified 11 novel AD risk loci, including four common variants and seven rare ones. Many of the exact genes differed from those identified in larger studies done on predominantly white participants, but their functions—in immunity, intracellular trafficking, and lipid processing—mostly overlapped. One exception was kidney development, which newly emerged in this study of black Americans.

  • AD GWAS in African Americans included 8,000 participants.
  • Of 11 novel risk loci identified, four were common, seven rare.
  • Immunity, trafficking, lipid processing, and kidney development implicated in disease risk.

Myriad factors likely contribute to higher dementia rates among black Americans (Tang et al., 2001). In addition to having a higher incidence of comorbidities such as hypertension and diabetes, this population is also disadvantaged in access to quality healthcare, education, and in socioeconomic status. Genetics might also play a role; alas, unearthing disease-associated variants requires massive numbers of samples, and the largest GWAS so far have included mostly non-Hispanic white populations (Oct 2018 conference news). 

In 2013, the Alzheimer’s Disease Genetics Consortium (ADGC), including authors of the current study, conducted a meta-analysis on more than 5,000 samples from African Americans collected across numerous case-control and family-based studies between 1989 and 2011 (Reitz et al., 2013). It pinned ApoE4 and ABCA7 as risk genes, and pulled out a novel variant in the intergenic region 5q35. A subsequent ADGC study reported that, among black Americans, those with AD had a higher degree of African ancestry than did unaffected people, suggesting that African genetics influenced disease (Hohman et al., 2015). 

Topping the sample size of the previous ADGC-run GWAS by 37 percent, this new one included 8,006 African Americans: 2,784 with AD, and 5,222 controls. Participants averaged 74 years of age at evaluation. This larger GWAS confirmed that single variants in ApoE, ABCA7, and 5q35 loci associated with AD.

It newly identified one rare variant that met the threshold for genome-wide significance. It is an intergenic locus positioned between the ARRDC4 and IGF1R genes. According to the Genome Aggregation Database, this variant, along with other variants near IGF1R that reached nominal significance in this GWAS, is only found in people of African ancestry. IGF1R encodes the insulin-like growth factor receptor, which influences stress resistance, aging, and lifespan. It has been tied to cognitive flexibility, an AD-related trait, in another study of African Americans (Holzenberger et al., 2003; Zhang et al., 2018). Multiple studies link aberrant IGF1 signaling to Aβ pathology and neurotoxicity (Talbot et al., 2012; Gontier et al., 2015). 

In addition, six new rare variants landed just below the significance threshold. They were near SIPA1L2, WDR70, API5, ACER3, PIK3C2G, and RBFOX1 genes. Furthermore, the GWAS loosely tied four new common variants to AD—one near the intracellular trafficking gene EDEM1, one within the immune response gene ALCAM, another within GPC6, a gene involved in recruiting glutamatergic receptors to the neuronal membrane; and one within VRK3, which encodes a kinase implicated in glutamate neurotoxicity. VRK3 has been proposed as a therapeutic target, as its dysregulation leads to Aβ accumulation (Song et al., 2016). 

Among loci previously tied to AD in non-Hispanic white people, besides ABCA7 and ApoE, only BIN1, FERMT2, and WWOX yielded variants with a nominal AD association in this sample of African Americans.

GWAS studies have long moved past merely enlisting the loci of Manhattan plots. They all attempt some form of analysis to draw insight from those lists. Kunkle et al. performed a gene-based analysis that took into account all variants near, or within, a gene instead of single variants. Seen through this lens, TREM2 was associated with AD at a genome-wide significant level, and eight other loci were tied to AD at a suggestive level.

To gauge which mechanisms might underlie these risk variants, the researchers analyzed their function. Eight pathways popped out: intracellular trafficking, lipid metabolism, transcription/DNA repair, nervous system development/synaptic plasticity, cell division, immune response, cellular signaling—and kidney system development. All except the latter had been pegged previously by larger GWAS, suggesting that, while individual risk variants may differ between white and black Americans, the major pathways implicated in Alzheimer’s are largely similar.

Then how to explain the link to kidney function? Not only are African Americans three times more likely to experience kidney failure than their white counterparts, but kidney disease also tracks more closely with dementia in this population (Laster et al., 2018; McAdams-DeMarco et al., 2018). Kidney dysfunction has been tied to brain Aβ accumulation (Pirici et al., 2017). 

Kunkle told Alzforum that kidney problems may be diagnosed at a later stage in African Americans, which could exacerbate downstream consequences for them, including AD. The kidney connection exemplifies how genetics, comorbidities, and healthcare disparities might converge to exacerbate AD risk, he noted.

Curiously, Aβ and tau pathways were conspicuously absent in this GWAS. Did it detect risk variants for non-AD dementia instead? Perhaps, Kunkle said. However, he noted that Aβ and tau pathways emerged in non-Hispanic white populations only once larger sample sizes were available for study.

Did the expression level of any of the GWAS hits associate with the burden of Aβ or tau pathology? Given that few African American brain tissue samples are available for study, the researchers used 478 samples from the predominantly white ROS-MAP cohort to address this question. They found that higher expression of ALCAM and ARAP1, and lower expression of GPC6 and RBFOX1, correlated with Aβ burden. Interestingly, RBFOX1 was recently tied to increased risk of amyloidosis (Jun 2020 news). Only STARD10, one of the genes with suggestive ties to AD risk, associated with higher tau burden.

Kunkle believes the field urgently needs to broaden ethnic diversity in genetic and clinical studies. Efforts are underway to recruit more non-white participants in the Alzheimer’s Disease Sequencing Project (ADSP) and into AD research studies and clinical trials (Cocroft et al., 2020; Gamboa et al., 2020; Lee et al., 2020; Gilmore-Bykovskyi et al., 2019). Researchers are also honing computational methods to analyze genomic data across multiple ethnicities (Jun et al., 2017; Wojcik et al., 2019). 

Kunkle added that future studies should focus on interactions between genetic risk variants and environmental stressors that disproportionately affect African Americans, including health, education, and socioeconomic disparities.

Carlos Cruchaga of Washington University in St. Louis noted that, while small, this GWAS suggests that additional disease genes and pathways can be identified by studying different populations. He added that while the risk variants found in this study may prove to be specific to African Americans, the genes and pathways uncovered by it are likely to play a role in AD more broadly. “I think that the identified genes will be implicated in disease independently of race, but if we want to identify all genes, we need to study different races,” Cruchaga wrote (see full comment below).—Jessica Shugart

Comments

  1. This is a very nice study. It is the largest GWAS in African Americans so far, though it is far below the sample size of the genetic studies from Europeans, which included almost 100,000 individuals.

    This study suggests that it is possible additional genes can be identified by studying different populations. This will lead to the identification of more genes and networks implicated in AD. If we want to identify all genes involved in Alzheimer’s risk, we need to study different races.

    Overall, I do not think this, or the European-focused studies, identifies race-specific genes and pathways. The variants reported here are specific to African Americans, but I think the identified genes will be implicated in disease independently of race. 

    The results we have so far are just the tip of the iceberg; larger studies will lead to many more hits. Larger studies will also allow more proper comparison of the genetic architecture of AD in African Americans versus non-Hispanic whites.

    My only minor concern with this study is that there is not a real replication study. Therefore, additional studies will be instrumental to confirm that the genes identified here are associated with AD in African Americans.

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References

News Citations

  1. Do African-Americans Have More, or Different, Alzheimer’s Disease? Too Little Data to Tell
  2. RBFOX1 Gene Tied to Amyloidosis in Preclinical Alzheimer’s

Paper Citations

  1. . Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology. 2001 Jan 9;56(1):49-56. 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. . Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk. Alzheimers Dement. 2015 Jun 16; PubMed.
  4. . IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003 Jan 9;421(6919):182-7. Epub 2002 Dec 4 PubMed.
  5. . Genome-wide association study of cognitive flexibility assessed by the Wisconsin Card Sorting Test. Am J Med Genet B Neuropsychiatr Genet. 2018 Jul;177(5):511-519. PubMed.
  6. . Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012 Apr 2;122(4):1316-38. PubMed.
  7. . Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance. J Neurosci. 2015 Aug 19;35(33):11500-13. PubMed.
  8. . VRK3-mediated nuclear localization of HSP70 prevents glutamate excitotoxicity-induced apoptosis and Aβ accumulation via enhancement of ERK phosphatase VHR activity. Sci Rep. 2016 Dec 12;6:38452. PubMed.
  9. . Kidney Disease Among African Americans: A Population Perspective. Am J Kidney Dis. 2018 Nov;72(5 Suppl 1):S3-S7. PubMed.
  10. . Dementia, Alzheimer's Disease, and Mortality after Hemodialysis Initiation. Clin J Am Soc Nephrol. 2018 Sep 7;13(9):1339-1347. Epub 2018 Aug 9 PubMed.
  11. . Common Impact of Chronic Kidney Disease and Brain Microhemorrhages on Cerebral Aβ Pathology in SHRSP. Brain Pathol. 2017 Mar;27(2):169-180. Epub 2016 May 30 PubMed.
  12. . Racially diverse participant registries to facilitate the recruitment of African Americans into presymptomatic Alzheimer's disease studies. Alzheimers Dement. 2020 Aug;16(8):1107-1114. Epub 2020 Jun 16 PubMed.
  13. . Proactive Recruitment of Older African-Americans for Alzheimer's Research with Brain Donation: a Cohort Case Study of Success. J Racial Ethn Health Disparities. 2020 Jun 25; PubMed.
  14. . The importance of diversity and outreach in geroscience research: Insights from the Annual Biomedical Research Conference for Minority Students. Geroscience. 2020 Jun;42(3):1005-1012. Epub 2020 May 3 PubMed.
  15. . Recruitment and retention of underrepresented populations in Alzheimer's disease research: A systematic review. Alzheimers Dement (N Y). 2019;5:751-770. Epub 2019 Nov 19 PubMed.
  16. . Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement. 2017 Jul;13(7):727-738. Epub 2017 Feb 7 PubMed.
  17. . Genetic analyses of diverse populations improves discovery for complex traits. Nature. 2019 Jun;570(7762):514-518. Epub 2019 Jun 19 PubMed.

Further Reading

Papers

  1. . Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk. Alzheimers Dement. 2015 Jun 16; PubMed.
  2. . Perceptions of Risk Factors for Alzheimer Disease Among Community-Dwelling, Nondemented Older African Americans. Alzheimer Dis Assoc Disord. 2019 Jul-Sep;33(3):254-259. PubMed.

Primary Papers

  1. . Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis. JAMA Neurol. 2020 Oct 19; PubMed.