This web page was produced as an assignment for an undergraduate course at Davidson College.

Assignment #1

Anti-Alzheimer's gene may have led to the rise of grandparents

    The research group of University of California, San Diego studied CD33, a gene that controls the body’s inflammatory and immune response. There are two variants of the gene, one predisposes a person to late-onset Alzheimer's disease (LOAD) while the other variant protects against it. To learn more about the gene’s lineage, they compared how prevalent the two variants were in human and chimpanzees, and discovered that both have similar amounts of the damaging version of CD33 even though primates do not seem to show the complete pathology of LOAD; however, the protective version is four times higher in humans, which might be compensatory to restore altered functions in humans. They also looked at the frequency of the protective version of CD33 in the 1000 Genomes Project, a database of human genetic variants of populations across the globe, and reveals the protective allele is found in a variety of ethnicities. Finally, they studied other genes that thought to protect against cognitive decline and vascular dementia in postreproductive humans and discovered that these variants also occur across ethnicities and were only found in humans (Burton, 2015; Schwarz et al., 2015).

Figure 1. PET scan showing the difference of brain structure between a normal older adult and an older adult with Alzheimer's disease.

Image courtesy of Wikimedia Commons via the National Institute on Aging.

Testing Hypothesis vs. Discovery Science    

    The research group arrived at their findings accidentally. They were studying the contribution of CD33 as an immunoregulatory receptor to Alzheimer's dementia and realized that our closest evolutionary relatives do not seem to suffer from the same type of cognitive decline, so they decided to compare the allelic state of CD33 in human and nonhuman primates and discovered that the protective variant of CD33 is derived and unique to human. After the discovery, they went on to study other alleles to see if the same pattern can be discerned (Schwarz et al., 2015).

Genomics Technology

    The research group performed genotyping to identify single nucleotide polymorphisms (SNPs) in the promoter region of CD33. They then retrieved human genomes from the 1000 Genomes Project and primate genomes from the Great Ape Genome and looked for the frequency of the protective allele of CD33 in both samples; they also analyzed the Neanderthal and Denisovan genomes. Additionally, they performed a polymorphism test at each gene and its surrounding region to identify patterns of polymorphism for each population and region (Burton, 2015; Schwarz et al., 2015). 

Take Home Message

    Late-onset Alzheimer's disease is considered to be unique to humans since postmortem brain samples reveal that chimpanzees and other great apes do not have the complete pathology of LOAD. This study shows that even though humans are more susceptible to particular neurodegenerative diseases, protective alleles are derived in humans to counteract and help restore some functions. Furthermore, since the protective allele is derived in humans, the study suggests that the protective variant probably evolved after humans first separated from our primate ancestors, and possibly after our common ancestor with Neanderthal and Denisovans approximately 550,000—765,000 years ago (Schwarz et al., 2015). 

    Different from most vertebrates, humans along with killer whales and pilot whales do not die immediately after their reproductive periods end and instead have prolonged lifespans. One theory, the grandmother hypothesis, tries to explain this phenomenon in humans, especially in women, suggesting grandmothers have a decidedly important role in the reproductive success of her children and the survival of her grandchildren (Burton, 2015). The grandmother hypothesis indicates the value of grandmothers and this study explains how longevity is achieved in some populations with genomic evidence. Moreover, the study suggests that the existence of a post-reproductive lifespan in humans can be interpreted as selection to maintain cognitive functions in elders (Schwarz et al., 2015).

Evaluation of this Project

    Overall, the project is valuable because it provides new insights into CD33's role in Alzheimer's disease with effective use of genome information and genomics technology. The study was also well-designed. They first examined the allelic state of CD33 to show that the protective allele is derived in humans, but they further support their statement with protein expression data. It was especially thoughtful that they studied several other genes that protect against neurodegenerative diseases, hypertension, diabetes and cardiovascular diseases. The findings make their conclusion more convincing since they discovered the pattern of derived protective alleles in humans.

    I think this project is especially meaningful because more than 5 million Americans over age 65 suffer from Alzheimer’s disease (Burton, 2015). Alzheimer’s disease is so complex that it cannot be prevented or cured; current approach can only help maintain mental function, manage behavioral symptoms, and delay symptoms (NIA, 2008).  Since CD33 is not found in every individual, the project can have great implication for preventing neurodegenerative diseases. Researchers can learn about these derived alleles and try to develop drugs that can mimic the effects of these protective alleles and possibly help prevent against neurodegenerative disease or cerebrovascular insufficiency in old age. This project also makes me wonder what other knowledge Genomics can offer. Genomics has already revolutionized the medical field in research of personalized medicine: by determining the specific genome sequence and interpreting the genetic variant, we can personalize diagnoses and offer the most effective treatment. This project's findings offer new insights on using genome information to provide medicines in preventive healthcare.

References

Burton KW. 2015. Anti-Alzheimer's gene may have led to the rise of grandparents. Science [Internet]. [cited 29 Jan 2016]. Available from: http://www.sciencemag.org/news/2015/11/anti-alzheimer-s-gene-may-have-led-rise-grandparents

National Institute on Aging. 2008. Alzheimer's Disease: Unraveling the Mystery [Internet]. Bethesda (MD): National Institutes of Health (US); [cited 29 Jan 2016]. Available from https://d2cauhfh6h4x0p.cloudfront.net/s3fs-public/alzheimers_disease_unraveling_the_mystery_0.pdf

Schwarz F, Springer S, Altheide T, Varki N, Gagneux Pm and Varki A. 2015. Human-specific Derived Alleles of CD33 and Other Genes Protect against Postreproductive Cognitive Decline. PNAS [Internet]. [cited 29 Jan 2016]; 113.1: 74-79. Available from: http://www.pnas.org/content/113/1/74.full