Brain Imaging Differences in Infants at Genetic Risk for Alzheimer's

Researchers from Brown University and Banner Alzheimer's Institute have found that infants who carry a gene associated with increased risk for Alzheimer's disease tend to have differences in brain development compared to children without the gene.

The researchers imaged the brains of 162 healthy infants between the ages of two months and 25 months. All of the infants had DNA tests to see which variant of the APOE gene they carried. Sixty of them had the E4 variant that has been linked to an increased risk of Alzheimer's. Using a specialized MRI technique, the researchers compared the brains of E4 carriers with non-carriers. They found that children who carry the APOE-E4 gene tended to have increased brain growth in areas in the frontal lobe, and decreased growth in areas in several areas in the middle and rear of the brain. The decreased growth was found in areas that tend to be affected in elderly patients who have Alzheimer's disease.

The researchers emphasized that the findings do not mean that any of the children in the study are destined to develop Alzheimer's or that the brain changes detected are the first clinical signs of the disease. What the findings do suggest, however, is that brains of APOE-E4 carriers tend to develop differently from those of non-E4 carriers beginning very early in life. It is possible that these early changes provide a "foothold" for the later pathologies that lead to Alzheimer's symptoms, the researchers say. Information from this study may be an important step toward understanding how this gene confers risk for Alzheimer's, something that is not currently well understood.

"This work is about understanding how this gene influences brain development," said Sean Deoni, who oversees Brown University's Advanced Baby Imaging Lab and was one of the study's senior authors. "These results do not establish a direct link to the changes seen in Alzheimer's patients, but with more research they may tell us something about how the gene contributes to Alzheimer's risk later in life."

The APOE-E4 variant linked to Alzheimer's is present in about 25 percent of the U.S. population. Not everyone who carries the gene gets Alzheimer's, but 60 percent of people who develop the disease have at least one copy of the E4 gene.

The gene is thought to have several different roles in the blood and brain, some of which remain to be clarified. For instance, it has been shown to participate in regulation of cholesterol, a molecule that is involved in the development of gray matter and white matter brain cells. It has also been shown to participate in the regulation of amyloid, a brain protein that accumulates in Alzheimer's and is now being targeted by investigational treatments. Studies are needed to clarify the ways in which APOE-E4, human development, aging and other risk factors may conspire to produce the brain changes involved in Alzheimer's disease.

The researchers used an MRI technique developed at Brown's Advanced Baby Imaging Lab. The technique quiets the MRI machine to a whisper, enabling the brains of healthy babies to be imaged while they sleep without medication. The technique also enables imaging of both gray matter -- the part of the brain that contains neurons and nerve fibers -- and white matter, which contains the fatty material that insulates the nerve fibers. Both gray and white matter are thought to have a role in Alzheimer's. White matter growth begins shortly after birth and is an important measure of brain development.

"We're in a good spot to be able to investigate how this gene influences development in healthy infants," said Deoni, assistant professor of engineering at Brown. "These infants are not medicated and not showing any cognitive decline -- quite the opposite, actually; they're developing normally."

There is no reason to believe that the children won't continue to develop normally, Deoni said. There is no consistent evidence to suggest that E4 carriers suffer any cognitive problems or developmental delay. And the areas of increased growth raise the possibility that the gene might actually confer some advantages to infants early on. Ultimately, the researchers hope the findings could lead to new strategies for preventing a disease that currently affects more than 5.2 million people in the U.S. alone.
"It may sound scary that we could detect these brain differences in infants," said Dr. Eric Reiman, executive director of the Banner Alzheimer's Institute in Arizona and another senior author on the paper. "But it is our sincere hope that an understanding of the earliest brain changes involved in the predisposition to Alzheimer's will help researchers find treatments to prevent the clinical onset of Alzheimer's disease -- and do so long before these children become senior citizens."

Your Liver May Be 'Eating' Your Brain

People with extra abdominal fat are three times more likely than lean individuals to develop memory loss and dementia later in life, and now scientists say they may know why.

It seems that the liver and the hippocampus (the memory center in the brain), share a craving for a certain protein called PPARalpha. The liver uses PPARalpha to burn belly fat; the hippocampus uses PPARalpha to process memory.

In people with a large amount of belly fat, the liver needs to work overtime to metabolize the fat, and uses up all the PPARalpha — first depleting local stores and then raiding the rest of the body, including the brain, according to the new study. The process essentially starves the hippocampus of PPARalpha, thus hindering memory and learning, researchers at Rush University Medical Center in Chicago.

In another study, researchers at Boston University School of Medicine found that the greater the amount of belly fat, the greater the brain shrinkage in old age. The surprising discovery in the new study is that the hippocampus uses PPARalpha to process memory and learning, and that this is a possible reason for the connection between belly fat and dementia and/or memory loss.

Rush University researchers, led by neurological sciences professor Kalipada Pahan, raised mice that were deficient in PPARalpha. Some mice had normal PPARalpha in the liver but depleted PPARalpha in the brain, and had poor memory and learning abilities. Others had normal PPARalpha in the brain but not the liver, and showed normal memory, as expected. When the researchers injected PPARalpha into the hippocampus of PPARalpha-deficient mice, their learning and memory improved, Pahan said.

"Further research must be conducted to see how we could potentially maintain normal PPARalpha in the [human] brain in order to be resistant to memory loss,"  PPARalpha thus provides a new avenue to explore in searching for a treatment or cure for Alzheimer's disease, dementia, and related memory-loss and cognition problems, Pahan said.

Can changes in the eyes help diagnose Alzheimer’s disease?

Diagnosing someone with Alzheimer’s disease can be a long and complicated process.  In addition to reviewing a patient’s full medical history, doctors must also subject individuals to expensive brain scans or invasive surgical procedures in order to be fully certain of the disease’s presence.

But now, there may be an easier way to spot the brain-wasting condition.  Researchers from Georgetown University Medical Center (GUMC) and the University of Hong Kong have found that it may be possible to diagnose Alzheimer's simply by screening for changes in two very important organs: the eyes.

“We’re looking for biomarkers for early disease [recognition], partly for our new clinical studies focusing more on prevention of Alzheimer’s… and to test new drugs,” study author Dr. R. Scott Turner, director of the Memory Disorder Program at GUMC.  “We’re hoping to incorporate this as a new biomarker for drug trials and potentially for screening and prognosis.”

Currently, there are two leading biomarkers that physicians can utilize to diagnose Alzheimer’s.  One is the buildup of beta-amyloid plaques in the brain, which can be observed through positron emission tomography (PET) or computed tomography (CT) scans.  The other involves measuring changes in protein levels of the cerebrospinal fluid – the liquid surrounding the brain and spinal cord.

However, brain imaging scans can be expensive for patients, and in order collect samples of the cerebrospinal fluid, doctors must administer a spinal tap, which can be a very invasive procedure.

Hoping to find a simpler biomarker, Turner and his colleagues decided to analyze the relationship between the eyes and dementia.  According to Turner, the retina serves as a direct extension of a person’s brain.

“The retinas have neurons themselves that send projections straight into the brain,” Turner said. “…Those nerve cells are directly connected to the brain via the optic nerve….So when looking at the retina, it’s the easiest place to see the brain and its neurons.”

Turner also noted that there has been an established association between glaucoma and Alzheimer’s, though the mechanisms behind the relationship remain unclear.  Most studies examining this connection have revolved around the retinal ganglion cell layer, which is responsible for transmitting visual information through the optic nerve.  However, this cell layer relies on information it receives from another layer in the retina called the inner nuclear layer, which had never before been studied in relation to dementia.

With this knowledge in mind, the researchers analyzed a group of mice that had been genetically engineered to develop Alzheimer’s disease, observing the thicknesses of the six layers in their retinas. They found that there was significant loss in thickness to both the inner nuclear layer, which experienced an average 37 percent loss of neurons, and the retinal ganglion cell layer, which experienced an average 49 percent loss.

According to Turner, these two retinal layers may be most vulnerable to neuron loss because they are larger than the other layers.

“The larger the neuron, the more vulnerable it seems to be to injury,” Turner said.  “We looked at some of the other [smaller] neurons, and they didn’t lose much because they were presumably less vulnerable. So we think whatever is killing neurons in the brain is killing the bigger nerve cells in the retina.”

The next step, Turner said, is to see if this biomarker translates to humans with Alzheimer’s.  If similar changes in retinal thickness occur in people, then a simple, noninvasive procedure known as optical coherence tomography (OCT) can be used to measure loss of neurons in these layers.

“If this holds true with humans and seems to be predicative, it could be used for screening, diagnosis, prognosis, but probably more immediately, a research tool to test new drugs,” Turner said. “…But we should probably be looking at the retinal thickness of our Alzheimer’s patients.”

Down Syndrome and Alzheimer's Disease Risk

Down syndrome increases the risk of Alzheimer’s disease. People with Down syndrome may experience health problems as they age that are similar to those experienced by older people in the general population. The presence of extra genetic material found among persons with Down syndrome may lead to abnormalities in the immune system and a higher susceptibility to certain illnesses, such as Alzheimer's, leukemia, seizures, cataracts, breathing problems, and heart conditions.

People with Down syndrome also experience premature aging. That is, they show physical changes related to aging about 20 to 30 years ahead of people of the same age in the general population. As a result, Alzheimer's disease is far more common in people with Down syndrome than in the regular population. Adults with Down syndrome often are in their mid to late 40s or early 50s when Alzheimer's symptoms first appear. People in the general population don't usually experience symptoms until they are in their late 60s.

The symptoms of Alzheimer's disease may be expressed differently among adults with Down syndrome. For example, in the early stages of the disease, memory loss is not always noted. In addition, not all symptoms ordinarily associated with Alzheimer's disease will occur. Generally, changes in activities of daily living skills are noted, and the person with Down syndrome may begin to have seizures when he or she never had them before. Changes in mental processes - such as thinking, reasoning, and judgment - also may be present, but they often are not commonly noticeable because of limitation of the individual's functioning in general.

Estimates suggest that 25% or more of individuals with Down syndrome over age 35 show the signs and symptoms of Alzheimer's-type dementia. The percentage increases with age. The incidence of Alzheimer's disease in people with Down syndrome is estimated to be three to five times greater than that of the general population.