'Jumping genes' hypothesis sheds new light on Alzheimer's

A team of Duke primate biologists and neurologists have uncovered "jumping genes" as potential strong contributors to the early stages of Alzheimer’s disease.

The investigators call their new model the "Alu neurodegeneration hypothesis"—named for Alu elements, a class of genes that can "jump" and insert themselves into new locations in the genome, acting as a common source of mutations in humans. The insertion of this element could disrupt normal cellular processes in the brain and may point to a biological basis behind the initial development of Alzheimer’s, explained Peter Larsen, co-author of the study and senior research scientist in biology professor Anne Yoder’s lab. 

Knowledge of this mechanism may help future researchers develop therapies to more effectively stem the beginning stages of the disease, Larsen explained.

“Our hypothesis is that this [Alu element] helps explain the very, very start of these diseases well before you could observe plaques and tangles forming," Larsen said. “This is something that can happen for years before you start to see a disease.”

The buildup of amyloid plaques and tangles in the brain has been the focus of the majority of past Alzheimer’s research, he noted.

However, this line of research has largely proved to be ineffective, said Michael Lutz, co-author of the study and assistant professor of neurology. According to a 2014 analysis examining Alzheimer's clinical trials, more than 99 percent of therapies tested between 2002 and 2012 failed despite initial promise.

“This class of drugs [to reduce plaque] just hasn’t seemed to work with respect to either improving the conditions of the patient or delaying the onset of the disease,” Lutz said.

Larsen noted that the study of Alzheimer's has begun to pivot in recent years to focus more on the molecular pathways leading to plaque development. One new target is the mitochondria—or the parts of the cell that produce energy. Larsen noted mitochondrial dysfunction can lead to neuron death and a variety of neurodegenerative diseases.

Larsen noted, however, that as humans age, the genetic mechanisms keeping Alu elements in check begin to falter. This suggests that the Alu element in the TOMM40 gene could be interfering with the production of certain important proteins later in life, eventually resulting in mitochondrial dysfunction and cell death.

“This particular type of variation in a gene could, in turn, over a long period of time set the stage for neurological dysfunction,” Lutz said.

Larsen explained that another powerful aspect of the study was its use of a lemur model instead of a typical mouse model. Lemurs are more closely related to humans from an evolutionary standpoint, which makes their findings less difficult to apply to humans.

Anne Yoder, professor of biology and director of the Duke Lemur Center, wrote in an email that their study revealed “an overdependence on the mouse as a model for studying the disease.” She added that rodents are too distantly related to humans to provide extensive insight into Alzheimer’s.

Larsen noted that although the mechanisms he and his collaborators have proposed are still preliminary, the group is hopeful that their findings could eventually lead to a revolution in how Alzheimer’s is treated.

“By looking at this different mechanism, you open up the possibility of using other classes of drugs, some of which might already might be out there for other applications,” Lutz said.

Larsen explained that drugs are only one method of potentially keeping Alu elements in check. A healthy lifestyle and diet also improve the body’s ability to stabilize the Alu elements and prevent them from wreaking havoc on the genome.

“[Those who live a healthy life] don’t show signs of cognitive impairment as early as people who are inactive and have an unhealthy lifestyle,” he said.