Study Reveals How Genetic Changes Lead to Familial Alzheimer's
Mutations in the presenilin-1 gene are the most common cause of inherited, early onset forms of Alzheimer’s disease. In a new study, published in Neuron, scientists replaced the normal mouse presenilin-1 gene with Alzheimer’s-causing forms of the human gene to discover how these genetic changes may lead to the disorder. Their surprising results may transform the way scientists design drugs that target these mutations to treat inherited or familial Alzheimer’s, a rare form of the disease that affects approximately 1 percent of people with the disorder. The study was partially funded by the National Institute of Neurological Disorders and Stroke.
For decades, it has been unclear exactly how the presenilin mutations cause Alzheimer’s disease. Presenilin is a component of an important enzyme, gamma secretase, which cuts up amyloid precursor protein into two protein fragments, Abeta40 and Abeta42. Abeta42 is found in plaques, the abnormal accumulations of protein in the brain that are a hallmark of Alzheimer’s. Numerous studies suggested that presenilin-1 mutations increased activity of gamma-secretase. Investigators have developed drugs that block gamma-secretase, but they have so far failed in clinical trials to halt the disease.
“The findings are a significant departure from conventional thinking that should open up exciting and creative new possibilities at all levels of research, from basic molecular mechanisms all the way to clinical intervention,” said Dr. Roderick Corriveau, program director at NINDS.
Eylea Outperforms Other Drugs for Diabetic Macular Edema
“Eylea, Avastin and Lucentis yield substantial gains in visual acuity for most people with diabetic macular edema; however, on average, Eylea appears to provide additional benefit for patients who start treatment with moderate or worse vision loss,” said study lead author Dr. John A. Wells.
In an NIH-supported clinical trial comparing three drugs for diabetic macular edema (DME), Eylea (aflibercept) provided greater visual improvement, on average, than did Avastin (bevacizumab) or Lucentis (ranibizumab) when vision was 20/50 or worse at the start of the trial. However, the three drugs resulted in similar average improvement when starting vision was 20/40 to 20/32. Investigators found no major differences in the safety of the three drugs. The trial was funded by the National Eye Institute. Additional funding was provided by NIDDK.
“This comparative effectiveness study will help doctors and patients make informed decisions when choosing treatments for diabetic macular edema,” said NEI director Dr. Paul Sieving. The results were published in the New England Journal of Medicine.
DME can occur in people with diabetic retinopathy, a type of diabetic eye disease that can cause the growth of abnormal blood vessels in the retina. The macula is the area of the retina used when looking straight ahead, for tasks such as reading, driving and watching television. Macular edema, or swelling, occurs when fluid leaks from retinal blood vessels and accumulates in the macula, distorting vision. Macular edema can arise during any stage of diabetic retinopathy and is the most common cause of diabetes-related vision loss. About 7.7 million Americans have diabetic retinopathy. Of these, about 750,000 have DME.
“Eylea, Avastin and Lucentis yield substantial gains in visual acuity for most people with diabetic macular edema; however, on average, Eylea appears to provide additional benefit for patients who start treatment with moderate or worse vision loss,” said Dr. John A. Wells, lead author of the study and a retinal specialist at Palmetto Retina Center, Columbia, S.C.
Physical Labor, Hypertension and Multiple Meds May Reduce Male Fertility
Working in a physically demanding job, having high blood pressure and taking multiple medications are among health risks that may undermine a man’s fertility, according to a study by researchers at NIH and Stanford University. The study is the first to examine the relationships between workplace exertion, health and semen quality as men are trying to conceive. The results were published online in Fertility and Sterility.
“Nearly 15 percent of U.S. couples do not become pregnant in their first year of trying,” said Dr. Germaine Buck Louis, the study’s senior author and director of the Division of Intramural Population Health Research at NICHD. “Male infertility plays a significant role and our aim is to explore the influence of environmental factors and health status on semen quality.”
Semen quality is a measure of a man’s ability to achieve fertilization and is based on the number, shape and movement ability of sperm, as well as other factors.
The investigators followed more than 500 couples in Texas and Michigan over a year-long period. The couples were in committed relationships and stopped using contraception. All male participants completed preliminary interviews in which they were asked about their reproductive history, health, lifestyle and occupational activity. Most of the men provided a semen sample for analysis.
“As men are having children later in life, the importance of diseases we once thought as separate from fertility must be re-explored,” said Dr. Michael L. Eisenberg, the study’s principal investigator and director of male reproductive medicine and surgery at Stanford. “Future investigations need to examine whether it’s the high blood pressure itself or the treatment that is driving these trends.”