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Genetic Analysis of Alzheimer's Disease

By: Sai Srihaas Potu

Alzheimer’s disease is the most common cause of dementia in older adults. Brain changes associated with the disease include abnormal clumps (amyloid-β plaques), tangled bundles of fibers (tau tangles), and the eventual death of nerve cells. These changes lead to a progressive decline in memory and thinking skills. First identified in 1907 by the German physician Alois Alzheimer, the illness impacts about 5 million Americans. An estimated one in nine adults aged 65 and older live with the disease.

A recent study suggests that controlling or preventing risk factors such as hypertension earlier in life may limit or delay the brain changes associated with Alzheimer’s disease and other age-related neurological deterioration.

Dr. Karen Rodrigue, assistant professor in the UT Dallas Center for Vital Longevity (CVL), was lead author on a study that looked at whether people with both hypertension and a common gene linked with Alzheimer’s disease (the APOE-4 gene carried by about 20 percent of the population) had more buildup of the brain plaque (amyloid protein) associated with Alzheimer’s disease. Many scientists believe the amyloid plaque is the first symptom of Alzheimer’s disease and shows up a decade or more before Alzheimer’s symptoms of memory impairment and other cognitive difficulties begin.

Until recently, amyloid plaque could only be seen at autopsy, but new brain scanning techniques allow scientists to see the amyloid plaque in the living brains of healthy adults. Findings from both autopsy and amyloid brain scans show that at least 20 percent of normal older adults carry elevated levels of amyloid, a substance made up mostly of protein and deposited in organs and tissues.

Based on evidence that hypertension was associated with Alzheimer’s disease, Rodrigue suspected that the double-whammy of hypertension and the presence of the APOE-4 gene might lead to particularly high levels of amyloid plaque in healthy adults.

Rodrigue’s research was part of the Dallas Lifespan Brain Study, a comprehensive study of the aging brain in a large group of adults of all ages funded by the National Institute on Aging. As part of this study, the research team recruited 147 participants (ages 30-89) to undergo cognitive testing, magnetic resonance imaging (MRI), and PET imaging. Using amyvid, a compound that when injected travels to the brain and binds with amyloid proteins, the scientists were able to visualize the amount of amyloid plaque. Blood pressure was measured at each visit.

Rodrigue classified participants in the study as hypertensive if they reported a current physician diagnosis of hypertension or if their blood pressure exceeded the established criteria for diagnosis. The participants were further divided between individuals who were taking antihypertensive medications and those who were not medicated but showed blood pressure elevations consistent with a diagnosis of hypertension. Finally, study subjects were classified in the genetic risk group if they were in the 20 percent of adults who had one or two copies of an APOE-4 allele, a genetic variation linked to dementia.

The most striking result of the study was that unmedicated hypertensive adults who also carried a genetic risk factor for Alzheimer’s disease showed much higher amyloid levels than all other groups. Adults taking hypertensive medications, even those with genetic risk, had levels of amyloid plaque equivalent to participants without hypertension or genetic risk.

The study suggests that controlling hypertension may significantly decrease the risk of developing amyloid deposits, even in those with genetic risk, in healthy middle-aged and older adults. Rodrigue noted that long-term studies of many people were needed to be certain that it was the use of hypertensive medications that led to decreased amyloid deposits. Nevertheless, this early finding provides a window into the potential benefits of controlling hypertension that goes beyond decreasing the risk of strokes and other cardiovascular complications.

Scientists cannot fully explain the neural mechanisms underlying the effect of hypertension and APOE-4 on amyloid accumulation. But earlier research in animal models showed that chronic hypertension may enable easier penetration of the blood-brain barrier, resulting in more amyloid deposition.

The recent study is significant because it focuses on a group of healthy and cognitively normal middle-aged and older adults, which enables the examination of risk factors and amyloid burden before the development of preclinical dementia. The team plans for long-term longitudinal follow-up with participants to determine which proportion of the subjects eventually develop the disease.

In the search for potential therapies, researchers have been studying known genetic causes of Alzheimer’s. Some rare forms of Alzheimer’s can be caused by variations in a single gene. These variants almost always cause symptoms by the time patients reach their 50’s—several decades earlier than the typical age of onset of the most common form of the disease.

Alzheimer’s disease is a progressive neurodegenerative condition. It is one of the most common forms of dementia. Alzheimer’s disease causes problems with a person’s ability to learn, reason, make judgments, communicate, and carry out daily activities.

People with Alzheimer's disease first develop subtle memory loss and personality changes that differ from normal age-related memory problems. They seem to tire or become upset or anxious more easily. They do not cope well with change. For example, they can follow familiar routes but travelling to a new place confuses them and they can easily become lost. In the early stages of the illness, people with Alzheimer's disease are particularly susceptible to depression. Further research needs to be conducted in order to help create better treatment and diagnosis options for patients with Alzheimer’s disease.


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2. Karen M. Rodrigue, Jennifer R. Rieck, Kristen M. Kennedy, Michael D. Devous, Ramon Diaz-Arrastia, Denise C. Park. Risk Factors for β-Amyloid Deposition in Healthy Aging Vascular and Genetic Effects. JAMA Neurology. 2013.

3. Reiman EM, Webster JA, Myers AJ. GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron. 2007.

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