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GENETIC & ENVIRONMENTAL FACTORS FOR ALZHEIMER’S DISEASE

Three different studies relating to amyloid beta and Alzheimer’s disease show potential risks and causes.

TWO NEW GENES:

An international team of scientists has identified two more genetic risk factors for Alzheimer’s disease. The group, reporting in Nature Genetics and including scientists from Washington University School of Medicine, completed the largest genome-wide association study ever involving patients with Alzheimer’s disease. The study pooled DNA samples from more than 19,000 older European and U.S. residents, 7,000 of whom had Alzheimer’s disease.

Prior to this study, only four genes had been definitively associated with Alzheimer’s disease. Three of the genetic mutations cause rare, inherited forms of early onset Alzheimer’s. The fourth gene, APOE4, was the only one linked to the more common late-onset form of the disease. By looking at more than 600,000 common DNA markers, study researchers were able to identify two new genes that appeared to be involved in elevated risk for Alzheimer’s and confirm the importance of APOE4.

“There’s good evidence that these new genes may be novel risk factors, the first discovered since APOE in 1993,” says Washington University researcher and co-author Alison M. Goate, DPhil, Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry and professor of neurology. The new genes identified in this study are APOJ, also called clustrin, on chromosome 8, and PICALM on chromosome 11.

Co-author John C. Morris, MD, Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and director of Washington University’s Alzheimer’s Disease Research Center (ADRC), says previous ADRC research suggests that the clustrin gene may be involved in the formation of amyloid deposits and plaques.

The other gene, PICALM, appears to be involved in the breakdown of synapses, which may be involved in the development of amyloid deposits. Goate says much more work is required to identify exactly how PICALM elevates Alzheimer’s risk. The study also identified 13 more gene variants worthy of further investigation.

SLEEP DEPRIVATION:

Chronic sleep deprivation in a mouse model of Alzheimer’s disease makes brain plaques appear earlier and more often, researchers reported in Science Express. They also found that the sleep-regulating protein orexin appears to be directly involved in the increase.

“Orexin or compounds it interacts with may become new drug targets for treatment of Alzheimer’s disease,” says senior author David M. Holtzman, MD, Andrew and Gretchen Jones Professor, chair of the Department of Neurology at Washington University and neurologist-in-chief at Barnes-Jewish Hospital.

Holtzman’s laboratory uses in vivo microdialysis to monitor levels of amyloid beta, the principal component of Alzheimer’s plaques, in the brains of mice genetically engineered as a model of Alzheimer’s disease. Lab members noticed that brain amyloid beta levels rose and fell in association with sleep and wakefulness, increasing in the night when mice are mostly awake.

A separate study of amyloid beta levels in human cerebrospinal fluid (CSF) led by Randall Bateman, MD, assistant professor of neurology, also showed that amyloid beta levels followed the same changes.

Blocking a hormone previously linked to stress and amyloid beta production had no effect on these changes. When orexin was injected into the brains of the mice, they stayed awake longer, and amyloid beta levels increased.

When researchers used the drug almorexant to block both orexin receptors, amyloid beta levels were significantly lower. “A treatment like this could be tested to see if it could delay the onset of Alzheimer’s disease,” Holtzman says.

Holtzman notes that not only does the risk of Alzheimer’s increase with age, the sleep/wake cycle also starts to break down. Investigators are considering epidemiological studies of whether chronic sleep loss in young and middle-aged adults increases risk of Alzheimer’s disease later in life. Holtzman also plans to learn more of the molecular details of how orexin affects amyloid beta.

BRAIN DAMAGE:

Washington University researchers have linked a potential indicator of Alzheimer’s disease to brain damage in humans with no signs of mental impairment. The results were published in the Annals of Neurology.

Although their cognitive and neurological assessments were normal, study participants with lower levels of amyloid beta 42 (A-beta 42) in their cerebrospinal fluid had reduced whole-brain volumes, suggesting that Alzheimer’s changes might already be damaging their brains.

In an earlier study, the same Washington University researchers showed that when A-beta 42 decreases in CSF, it begins to build up in the brain.

“The new results show that something associated with amyloid deposition in the brain-—either the amyloid itself or some toxic product of it—is causing brain damage in people who are still cognitively normal,” says senior author David M. Holtzman, MD.

For the study, led by Anne Fagan, PhD, research associate professor of neurology, researchers analyzed CSF samples and took MRI scans of subjects’ brains to determine whole-brain volume. Participants with normal levels of A-beta 42 in their CSF had whole-brain volumes within expected ranges. But in both the cognitively impaired subjects and in cognitively normal volunteers with decreased CSF A-beta 42, the size of the brain was smaller.

In addition to A-beta 42, researchers analyzed CSF levels of tau proteins and neurofibrillary tangles that increase as Alzheimer’s disease progresses. Scientists believe increased levels of tangles in the brain lead to increased CSF tau levels.

“We’ve thought for some time that in Alzheimer’s disease, amyloid builds up first, followed by an increase in tangle accumulation,” Holtzman says.

“This is some of the first evidence in living people that this idea may be right: Large- scale changes in amyloid seem to precede Large-scale changes in tau, which are then linked to the onset of clinical dementia symptoms.”  he says.

Researchers will follow subjects to see if they eventually become demented, potentially confirming A-beta 42 as an antecedent biomarker for Alzheimer’s disease.

Harold D, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nature Genetics, advance online publication. Sept. 6, 2009. Kang J-E, et al. Amyloid beta dynamics are regulated by orexin and the sleep-wake cycle. Science Express, Sept. 24, 2009.

Fagan AM, et al. Decreased cerebrospinal fluid amyloid beta 42 correlates with brain atrophy in cognitively normal elderly. Annals of Neurology, online publication.

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