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Research led by Dr. Linda Chang: Alzheimer’s gene may show effects on brain starting in childhood

Date: July 13th, 2016 in Breakthoughs, Faculty, JABSOM News, Research    Print or PDF

The image of a child's brain captured at The Queen's-UH MR Center.

A gene associated with Alzheimer’s disease and recovery after brain injury may show its effects on the brain and thinking skills as early as childhood, according to a study published in the July 13, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Prior studies showed that people with the epsilon(ε)4 variant of the apolipoprotein-E gene are more likely to develop Alzheimer’s disease than people with the other two variants of the gene, ε2 and ε3.

“Studying these genes in young children may ultimately give us early indications of who may be at risk for dementia in the future and possibly even help us develop ways to prevent the disease from occurring or to delay the start of the disease,” said study author Linda Chang, MD, of the University of Hawaiʻi in Honolulu and a Fellow of the American Academy of Neurology.

For the study, 1,187 children ages 3 to 20 years had genetic tests and brain scans and took tests of thinking and memory skills. The children had no brain disorders or other problems that would affect their brain development, such as prenatal drug exposure. The largest group of children, 250 of them (roughly 20% of the entire study cohort) were tested at the University of Hawai’i – Queen’s Medical Center MR Research Center.

Study Details
Each person receives one copy of the gene (ε2, ε3 or ε4) from each parent, so there are six possible gene variants: ε2ε2, ε3ε3, ε4ε4, ε2ε3, ε2ε4 and ε3ε4.

The study found that children with any form of the ε4 gene had differences in their brain development compared to children with ε2 and ε3 forms of the gene. The differences were seen in areas of the brain that are often affected by Alzheimer’s disease.

In children with the ε2ε4 genotype, the size of the hippocampus, a brain region that plays a role in memory, was approximately 5% smaller than the hippocampi in the children with the most common genotype (ε3ε3). The children younger than age 8 years and with the ε4ε4 genotype typically had lower measures on a brain scan that shows the structural integrity of the hippocampus.

“These findings mirror the smaller volumes and steeper decline of the hippocampus volume in the elderly who have the ε4 gene,” Chang said.

In addition, some of the children with ε4ε4 or ε4ε2 genotype also had significantly lower scores on some of the tests of memory and thinking skills. Specifically, the youngest ε4ε4 children had up to 50% lower scores on tests of executive function and working memory, while some of the youngest ε2ε4 children had up to 50% lower scores on tests of attention. However, children older than 8 years with these two genotypes had similar and normal test scores compared to the other children.

Limitations of the study include that it was cross-sectional, meaning that the information is from one point in time for each child, and that some of the rarer gene variants (e.g. ε4ε4, ε2ε4) and age groups did not include many children.

“So one limitation is because those genes … happen to be extremely rare,” said Dr. Chang. “… And even though we have a large sample size of 1,200 children, the group of those who had these rare genotypes are pretty small. So it would be good to replicate the study in a bigger cohort of children and also to follow them over time.”

Dr. Chang said the findings do not suggest parents should seek out genetic tests for their children. “Right now it’s not appropriate to test children for the gene because we are still in a research stage, we are still trying to understand how the gene affects brain development,” said Chang. “Also, the genes that we are talking about that we are studying is just aspect of many factors that could contribute to Alzheimer’s disease.”

Dr. Chang in the control room of the University of Hawai'i - Queen's Medical Center MR Research Center.

Dr. Chang in the control room of the University of Hawai’i – Queen’s Medical Center MR Research Center.

The study was supported by the National Institutes of Health, including the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute on Child Health and Human Development.

See UH-Queen’s Medical Center MR Research Center photos.

Frequently Asked Questions

Link between gene variant and Alzheimer’s may show effects on the brain as early as childhood

1. What is the significance on the findings in the study on the link between a certain gene and Alzheimer’s disease?
The study looked at children with genotypes (e.g., APOE ε 4 ε 4 and APOE ε 2 ε 4) that are more common in people with Alzheimer’s disease. These children show slightly delayed brain development and cognitive function during early ages (before ages 8-10 years). Therefore, these findings indicate that these genes not only can influence the development of Alzheimer’s disease later in life, but can also affect early brain development.

2. How was the gene identified?
The gene was not “identified.” The APOE- ε 4 gene is a well known gene that has been studied by many researchers in relation to Alzheimer’s disease. The investigators studied the effects of this genotype (six total) on brain structure and function in typically developing children.

3. What impacts does this gene have on brain development?
Younger children with the genotypes that are more common in individuals with Alzheimer’s disease had slower brain development in brain regions often affected in patients with Alzheimer’s. Please note that each genotype involves two genes in each individual, one from each parent (e.g., APOE- ε 4 ε 4 or APOE- ε 2 ε 4)

4. What ethical considerations do researchers or medical professionals have to take into account when children are found to be a positive match for the ε4 gene? The researchers do not recommend checking for these genotypes in any children until there are established methods to improve their brain function or to prevent the development of Alzheimer’s disease later in life. Studies such as this one is to provide a better understanding on how these genes might influence brain development and later brain aging. Also, it is important to emphasize that the older children with these genotypes showed normal brain structure and function.

5. What could the findings of the study mean for potential preventative measures to stop the disease from occurring?
The findings of this study might provide early indications of who might benefit from preventive measures when they become available. These individuals might also want to avoid activities that might lead to traumatic brain injury.

6. What other factors aside from genetics contribute to the onset of Alzheimer’s disease?
Many other genes and factors have been shown to increase the risk for Alzheimer’s disease. Other factors include age (i.e., increase risk with older age), diet and lifestyle (e.g., exercise), which are thought to be responsible for the decreased incidence of dementia in the U.S. and in Europe.

7. What are the next steps in this research?
Follow-up (longitudinal) studies are needed to evaluate whether the findings in the current cross-sectional study are valid. Also, since the rarer genotype groups had fewer children, the researchers would like to replicate this study in a larger cohort of children.


To learn more about brain health, please visit http://www.aan.com/patients.

The American Academy of Neurology, the world’s largest association of 30,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit http://www.aan.com.

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