Carriers of Alzheimer's genetic marker have greater difficulty harnessing past knowledge
August 22, 2019
Science Daily/Baycrest Centre for Geriatric Care
Adults carrying a gene associated with a higher risk of Alzheimer's disease had a harder time accessing recently acquired knowledge, even though they didn't show any symptoms of memory problems, according to findings published in a joint Baycrest-University of Oxford study.
Researchers found that older adults carrying a specific strain of the gene, apolipoprotein E4, otherwise known as APOE4, weren't able to tap into information they had just learned to assist them on a listening test.
These findings suggest greater difficulty for these individuals to access knowledge from their memory to guide their attention in ways that would have improved their performance, according to the study published in the journal Scientific Reports. This work could lead to the development of new ways to detect individuals at risk.
The research team worked with 60 research participants (aged 40 to 61) from the Oxford Biobank who had varying combinations of APOE genes -- which includes one group of individuals with a combination of APOE3/APOE4 genes, one group of individuals with a set of APOE4 genes and one group of individuals with a set of APOE3 genes. All research participants had normal hearing, scored within the normal range of cognitive assessments and completed a questionnaire about their memory.
Each research participant listened to 92 audio clips and they were told to pay attention to where the clip was coming from, whether it was presented in the left, right or both ears. After the clip was played, they were asked which side they heard the sound from and if they responded incorrectly, the sound was replayed. Participants had a one-hour break before hearing the 92 audio clips again, but this time they were asked whether there was an additional sound at the end of the clip and to press a button when they heard it. Each clip was placed twice. During the first play-through, the clip's location was replayed and during the second play-through, the additional tone was added.
The study found that no matter the APOE genotype, all older adults were able to learn the information and remember the location of the audio clip, but individuals with the APOE4 gene had greater difficulty in identifying the additional sound at the end of the clip.
"For some reason, people with the APOE4 gene were not able to take advantage of information they learned earlier, such as the expected location of the clip, to boost their performance," says Dr. Claude Alain, a senior author on the paper and senior scientist at Baycrest's Rotman Research Institute. "This study shows we have a test that is sensitive to capture problems or challenges faced by individuals with this gene, before their deficits are observed on a standard neuropsychological assessment."
This was an exciting study looking at healthy, middle-aged people who carry a gene that increases their risk of developing Alzheimer's disease by 15-fold, says Dr. Chris Butler, a senior author on the paper and an associate professor in clinical neurosciences at the University of Oxford.
"The research could lead to more sensitive methods of detecting Alzheimer's disease in its very earliest stages, the time at which treatments are most likely to be effective," says Dr. Butler. "I was delighted to carry out this work with researchers from Baycrest."
As next steps, researchers continue to explore how the brain's ability to process what is heard changes with neurodegenerative conditions, such as mild cognitive impairment.
https://www.sciencedaily.com/releases/2019/08/190822141908.htm
Impaired learning linked to family history of Alzheimer's
July 10, 2019
Science Daily/eLife
Adults with a first-degree relative with Alzheimer's disease perform more poorly on online paired-learning tasks than adults without such a family history, and this impairment appears to be exacerbated by having diabetes or a genetic variation in the apolipoprotein E (APOE) gene linked to the disease.
The findings, published on Tuesday in eLife, may help identify people who have increased risk for developing Alzheimer's disease and could uncover new ways to delay or prevent the disease.
"Identifying factors that reduce or eliminate the effect of a family history of Alzheimer's disease is particularly crucial since there is currently no cure or effective disease-slowing treatments," says lead author Joshua Talboom, PhD, a Postdoctoral Fellow at the Translational Genomics Research Institute in Arizona, US.
Having a family history of Alzheimer's disease is a well-known risk factor for developing the condition, but the effects on learning and memory throughout a person's life are less clear. Some studies have been conducted in this area, but most have been too small to draw significant conclusions.
To enable a larger study, Talboom and colleagues created an easy-to-use website, http://www.mindcrowd.org, that participants could log on to and complete a memory test. Participants were asked to learn 12-word pairs and were then tested on their ability to complete the missing half of the pair when presented with one of the words.
The 59,571 individuals who participated were also asked to answer questions about their sex, education, age, language, country and health, including a question about whether one of their parents or siblings had been diagnosed with Alzheimer's disease. Those with a family history of Alzheimer's were able to match about two and one-half fewer word pairs than individuals without a family history. Having diabetes appeared to compound the learning impairments seen in individuals with a family history.
A subset of 742 participants who had a close relative with Alzheimer's submitted a sample of dried blood or saliva that the researchers tested for a genetic variation in the APOE gene linked to the disease. "The APOE genotype is an important genetic factor that influences memory, and we found that those with the variation performed worse on the memory test than those without the variation," Talboom explains.
Some characteristics, however, appeared to protect against memory and learning impairments in people with a family history of Alzheimer's disease. Participants with higher levels of education experience less of a decline in scores on the learning and memory test than people with lower levels of education, even when they have a family history of the disease. Women also appear to fair better despite having Alzheimer's disease risk factors.
"Our study supports the importance of living a healthy lifestyle, properly treating diseases such as diabetes, and building learning and memory reserve through education to reduce the cognitive decline associated with Alzheimer's disease risk factors," concludes senior author Matthew Huentelman, Professor of Neurogenomics at the Translational Genomics Research Institute, Arizona.
https://www.sciencedaily.com/releases/2019/07/190710131936.htm
High LDL linked to early-onset Alzheimer's
May 28, 2019
Science Daily/Veterans Affairs Research Communications
Researchers with the Atlanta Veterans Affairs Medical Center and Emory University have found a link between high LDL cholesterol levels and early-onset Alzheimer's disease. The results could help doctors understand how the disease develops and what the possible causes are, including genetic variation.
According to Dr. Thomas Wingo, lead author of the study, the results show that LDL cholesterol levels may play a causal role in the development of Alzheimer's disease.
The results appear in the May 28, 2019, issue of JAMA Neurology.
"The big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer's disease risk," says Wingo. "The existing data have been murky on this point. One interpretation of our current data is that LDL cholesterol does play a causal role. If that is the case, we might need to revise targets for LDC cholesterol to help reduce Alzheimer's risk. Our work now is focused on testing whether there is a causal link."
Wingo is a neurologist and researcher with the Atlanta VA and Emory University.
Elevated cholesterol levels have been linked to increased risk of Alzheimer's later in life. This risk may be due to genetic factors tied to cholesterol. Past research has shown that a major risk factor for Alzheimer's disease is a specific mutation in a gene referred to as APOE. It is the largest known single genetic risk factor for Alzheimer's disease. This APOE variant, called APOE E4, is known to raise levels of circulating cholesterol, particularly low-density lipoprotein (LDL). This type of cholesterol is sometimes referred to as "bad cholesterol" because high LDL levels can lead to a build-up of cholesterol in the arteries.
While late-onset Alzheimer's -- the common form of the disease -- appears to be linked to cholesterol, little research has been done on a possible connection between cholesterol levels and early-onset Alzheimer's risk.
Early-onset Alzheimer's is a relatively rare form of the condition. The disease is considered "early-onset" when it appears before age 65. About 10% of all Alzheimer's cases are early-onset. Past research has shown that the condition is largely genetics-based, meaning it is likely to be inherited if a parent has it.
Three specific gene variants (dubbed APP, PSEN1, and PSEN2) are known to be related to early-onset Alzheimer's disease. APOE E4 is also a risk factor in this form of the disease, as well. These gene variants explain about 10% of early-onset Alzheimer's disease cases, meaning that 90% of cases are unexplained.
To test whether early-onset Alzheimer's disease is linked to cholesterol and identify the genetic variants that might underlie this possible association, the researchers sequenced specific genomic regions of 2,125 people, 654 of whom had early-onset Alzheimer's and 1,471 of whom were controls. They also tested blood samples of 267 participants to measure the amount of LDL cholesterol.
They found that APOE E4 explained about 10% of early-onset Alzheimer's, which is similar to estimates in late-onset Alzheimer's disease. The researchers also tested for APP, PSEN1, and PSEN2. About 3% of early-onset Alzheimer's cases had at least one of these known early-onset Alzheimer's risk factors.
After testing blood samples, the researchers found that participants with elevated LDL levels were more likely to have early-onset Alzheimer's disease, compared with patients with lower cholesterol levels. This was true even after the researchers controlled for cases with the APOE mutation, meaning cholesterol could be an independent risk factor for the disease, regardless of whether the problematic APOE gene variant is present.
The researchers did not find a link between HDL (high-density lipoprotein) cholesterol levels and early-onset Alzheimer's, and only a very slight association between the disease and triglyceride levels.
The researchers also found a new possible genetic risk factor for early-onset Alzheimer's disease. Early-onset Alzheimer's cases were higher in participants with a rare variant of a gene called APOB. This gene encodes a protein that is involved in the metabolism of lipids, or fats, including cholesterol. The finding suggests a direct link between the rare APOB mutation and Alzheimer's disease risk, according to the researchers. However, the link between LDL-C level and early-onset Alzheimer's was not fully explained by APOE or APOB, suggestion that other genes and mechanisms also increase disease risk.
While the study shines light on possible risk factors for early-onset Alzheimer's disease, the researchers say that more research is needed to fully explain the connection between the disease and cholesterol. The relative rarity of early-onset Alzheimer's disease presents a challenge in finding enough samples to perform large genetic studies on the condition, they say.
https://www.sciencedaily.com/releases/2019/05/190528120558.htm