Brain changes wrought by gene linked to Alzheimer’s may begin in childhood, scientists say


The gene that makes some people more vulnerable to Alzheimer’s disease as adults also affects the brain development and mental abilities of children, a new study shows.

Researchers who examined brain scans of 1,187 kids and teens found distinct patterns in the size and structure of the cortex, hippocampus and other important structures. These patterns were linked with different versions of a gene known as APOE, which may play a role in up to 25% of Alzheimer’s cases.

The research team also found a relationship between the version of APOE each young person had and how well each did on tests to measure cognitive function, working memory and attention.


The findings, published Wednesday by the journal Neurology, suggest that Alzheimer’s may be much more than a disease related to the brain’s inability to clear beta amyloid plaques. Instead, it may be useful to think of it as a developmental disorder.

The APOE gene tells cells how to make a protein called apolipoprotein E. When constructed, this protein helps form the molecules that carry cholesterol and other fats through the bloodstream. These molecules also ferry beta amyloid out of the brain.

The gene comes in three varieties, known as the e2, e3 and e4 variants. Since everyone inherits one version of the gene from each parent, there are six possible combinations. People with one — and especially two — e4 variants are significantly more likely to develop Alzheimer’s than people without e4. Researchers also have found that adults with e2 variants have more plaques in their brains but are less likely to have symptoms of dementia.

A team led by Dr. Linda Chang, director of the Neuroscience and MRI Research Program at the University of Hawaii, wanted to see whether these gene variants influenced the brains of people earlier in life. So they recruited healthy subjects age 3 to 20 from around the country and enrolled them in the Pediatric Imaging, Neurocognition, and Genetics Study.

All of the children and teens in the study gave saliva samples so researchers could sequence their DNA. They took a series of tests to measure various aspects of cognitive function, and they got MRI scans so that researchers could visualize their brains.

The researchers found a variety of differences in mental abilities and brain structure based on the age of the children and their particular version of the APOE gene. Many differences held up even after the researchers controlled for things like gender, genetic ancestry, family income and parents’ education.


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They found that children with e4/e4, e2/e2 and e2/e4 versions of the APOE gene showed different trajectories of brain development than children who inherited at least one e3 variant. The affected brain regions were ones that often are affected by Alzheimer’s as well, according to the study.

Younger children with e2/e4 had less volume in the part of the brain called the hippocampus, which helps store information in long-term memory. In the same part of the brain, younger children with e4/e4 appeared to have a lower degree of myelination, which would hinder the transmission of signals between neurons. Both of these conditions “mirror” the brains of elderly people with the same genetic variants, the researchers wrote.

The study authors also noted that younger children with these two APOE variants and altered brain development also got lower scores on tests of their working memory and attention.

In addition to other brain differences, younger e4/e4 children also had signs of atypical development in the cortex — signs that are seen in kids with fetal alcohol syndrome.

The study authors made inferences about brain development by comparing children at different ages. Since brain development can vary quite a bit from person to person, it would be valuable to track individual children over a long period of time, they wrote.


Even with that caveat, the study results are “extremely intriguing,” according to an editorial that accompanies the findings.

The results “support the provocative idea that AD (Alzheimer’s disease) is, in part, a developmental disorder,” wrote brain researchers Rebecca Knickmeyer of UNC Chapel Hill and Dr. M. Elizabeth Ross of Weill Cornell Medical College.

If so, they wrote, it may be possible to develop treatments for children with high-risk DNA variants that would — decades later — delay the onset of Alzheimer’s, reduce its severity or prevent it altogether.

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