By Max Wallack
Puzzles to Remember
Many diseases are caused, at least in part, by bad genes, including phenylketonuria, alkaptonuria, Tay-Sachs disease, porphyria, and early-onset Alzheimer's.
Other conditions, like late-onset Alzheimer's, have complex causes, but certain genes are known to increase the risks.
Biologists have long wondered, if conditions like these are harmful, why hasn't natural selection eliminated them from our populations?
In case after case, it turns out that the allele, or gene variation, responsible for a disease sometimes confers a benefit that may explain why natural selection has not weeded it out of the population.
The best-studied example of this phenomenon is sickle-cell anemia, a disease caused by a mutation, HbS, in the gene for hemoglobin. Red blood cells in people who have two copies of the HbS allele have a greatly reduced oxygen-carrying ability, and under certain conditions they assume deformed, sickle-like shapes that clog the body's capillaries and produce painfully swollen joints, deformed skull bones, and an enlarged spleen. Without the proper drugs, people with sickle-cell anemia usually die before adulthood.
The HbS allele, however, is relatively frequent in many parts of Africa (and also in Laos and Cambodia). It turns out that a single copy of the HbS allele greatly reduces the chances of being bitten by malaria-carrying mosquitoes, or of actually getting malaria even if bitten. In swampy places where malaria mosquitoes abound, natural selection favors the HbS/HbA (heterozygous) condition, explaining the high prevalence of the HbS allele in many parts of the world. Other disease-causing genes that confer resistance to malaria include those causing thalassemia and G6PD deficiency.
Other possible examples are numerous. The gene that causes Tay-Sachs disease is thought to confer a degree of resistance to tuberculosis, a disease that once ravaged many European populations and that still persists in several of the poorest parts of the world. The gene causing cystic fibrosis is thought to have protected Medieval populations against the bubonic plague, and possibly also against tuberculosis
Huntington's disease is a genetic disorder that kills its victims after age 40, but the gene persists in many human populations because the people who eventually die from Huntington's may have a reproductive advantage and often have a greater-than-average number of children before they get the disease.
The Rh factor is a blood cell antigen that causes many infant deaths each year if an rh-negative mother makes antibodies against her Rh-positive baby. As in Huntington’s disease, the condition persists in the population because rh-negative mothers seem, on average, to have more children than other women.
One of the genes commonly associated with late-onset Alzheimer's disease is called ApoE4. Recent discoveries have shown that the ε4 allele of this gene, even when present in just a single copy, enhances memory performance in healthy teenagers, compared to the more common ε2 and ε3 alleles (see references at the end of this article).
In other words, the allele has cognitive benefits in terms of efficient memory earlier in life, but increases the risk of Alzheimer's disease much later in life. The same allele also reduces the chances of certain infections, including Chlamidia.(the most common sexually transmitted infection) and Giardia (a parasitic disease).
People who could avoid these infections and could learn better and remember more efficiently in their teens or young adult years might leave more children, even if they were destined to have Alzheimer's disease in old age. Natural selection would favor such an allele, especially in times past, when average longevity was well below 60 years and few people lived old enough to develop Alzheimer's.
Another, much rarer gene, TREM2, has recently come to light in Europe. Certain people in Iceland, Norway, and several other countries suffer from a condition, sclerosing leucoencephalopathy, in which the bones break down internally and an unusual dementia begins around 40-45 years of age. The dementia begins very slowly, but worsens dramatically after a few years and usually causes death before age 50.
Researchers studying the families of people with this disease found that carriers of the allele responsible for the disease were likely to develop Alzheimer's disease. Researchers also found that the normal allele of this gene helps maintain certain types of cells, including white blood cells, bone-eating osteoclasts, and microglial cells in the brain. The microglia patrol brain tissue and scavenge away the amyloid beta whose buildup forms the plaques that causes Alzheimer's disease. The mutated version of the TREM2 gene interferes with this scavenging activity, allowing the amyloid beta to accumulate and cause Alzheimer's.
Researchers who study the immune system are hopeful that studies of this scavenging activity in the brain can lead to a treatment for late-onset Alzheimer's.
- Better Memory and Neural Efficiency in Young Apolipoprotein E ε4 Carriers
- Better Episodic Memory in Young E4s
- The Biology of Human Longevity:: Inflammation, Nutrition, and Aging in the Evolution of Lifespans
- Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper
- Brain gene APOE e4 linked to dementia
- Mutation Raises Alzheimer's Risk
- Alzheimer’s Tied to Mutation Harming Immune Response
- New gene holds promise for understanding Alzheimer's
- Variant of TREM2 Associated with the Risk of Alzheimer's Disease
- Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles
- Gene mutation identified as new risk factor for Alzheimer's
- TREM2 Variants in Alzheimer's Disease
Max Wallack is a student at Boston University and a Research Intern in the Molecular Psychiatry and Aging Laboratory in the Department of Pharmacology and Experimental Therapeutics at
Boston University School of Medicine. His great grandmother, Gertrude, suffered from
Alzheimer's disease. Max is the founder of PUZZLES TO REMEMBER. PTR is a project that provides puzzles to nursing homes and veterans institutions that care for Alzheimer's and dementia patients.