DURHAM, N.C.—The latest round of failed drug trials for Alzheimer’s disease has researchers questioning the reigning approach to battling the disease, which focuses on preventing amyloid buildup in the brain. A large Eli Lilly trial with the drug solanezumab recently reported failure to note statistically significant improvement, although according to the New York Times, Dr. Reisa Sperling notes patients did improve somewhat on solanezumab. She plans to evaluate the data to see if changes to the design of the trial should be made.
Merck also announced in February that its trial for verubecestat was unsuccessful, with “virtually no chance of success,” according to an article in Science. The company still plans to run a separate Phase 3 study in prodromal patients, as investigators didn’t find any safety issues with verubecestat.
Duke University scientists have identified a mechanism that could explain how neurons begin to falter in the initial stages of Alzheimer’s, even before amyloid clumps appear. This rethinking of the Alzheimer’s process centers on human genes critical for the healthy functioning of mitochondria, which are riddled with mobile chunks of DNA called Alu elements.
Dr. Peter A. Larsen, senior research scientist in the Department of Biology at Duke University tells DDNews, “In 2004, Swerdlow and Khan provided a unifying hypothesis, rooted in mitochondrial dysfunction, for the origin of sporadic Alzheimer’s disease—the mitochondrial cascade hypothesis—and it states that mitochondrial dysfunction drives amyloid beta plaque formation, neurofibrillary tangle formation and other pathologies observed in sporadic Alzheimer’s disease.”
The dominant idea guiding Alzheimer’s research for 25 years has been that amyloid buildup in the parts of the brain that control memory causes the disease. But failing anti-amyloid drug trials have led some researchers to theorize that amyloid buildup is a byproduct, not a cause.
“Despite observations that link mitochondrial dysfunction and sporadic neurodegenerative disease, there hasn’t been a robust hypothesis that could explain the origin of mitochondrial stress associated with human aging and able to account for neurological disease observed across the entire human population,” Larsen continues. “The ‘Alu neurodegeneration hypothesis’ provides this link. Alus belong to a class of retrotransposons or mobile elements. They get the name ‘jumping gene’ because they can move about the genome and insert themselves into new locations. Alus are found only in primates, and they are abundant in the human genome (approximately 11 percent of human DNA). For a long time, they were considered junk DNA because their function was largely unknown. Only recently has the scientific community begun to appreciate how much Alu elements have influenced human evolution.”
If this Alu neurodegeneration hypothesis holds up, it could help identify people at risk sooner, before they develop symptoms, or point to new ways to delay onset or slow progression of the disease, says Larsen.
“Alu elements play an important role in gene function and regulation. It’s hypothesized that mobile elements, including Alus, have shaped the evolution of the human brain. Despite the benefits that Alus can have with respect to gene diversity and protein function, they can also cause disease,” Larsen notes. “The Alu neurodegeneration hypothesis shows how Alu elements can impact mitochondrial function in the central nervous system over time, increasing with age, and therefore potentially impacting neuron stability.”
“The human genome controls Alu elements in part through epigenetic regulation. The hypothesis states that Alu elements within nuclear-encoded mitochondrial genes can directly impact mitochondrial function and should be considered for the origin of sporadic neurodegenerative disease. Also, the jumping of Alu elements is only one small part of how they can influence gene function. Most of the jumping and landing has already occurred in our genome; it’s a combination of many complex downstream processes that influence gene function and cause disease. Most of the action with Alus likely correlates with eroding epigenetic landscapes associated with aging,” he adds.
Most mitochondrial proteins are encoded by genes in the cell nucleus before reaching their final destination in mitochondria. In 2009, Duke neurologist and study co-author Allen Roses, who passed in October 2016, identified a non-coding region in a gene called TOMM40 that varies in length. Roses and his team found that the length of this region can help predict a person’s Alzheimer’s risk and age of onset.
Larsen wondered if the length variation in TOMM40 was only part of the equation. He analyzed the corresponding gene region in gray mouse lemurs, teacup-sized primates known to develop amyloid brain plaques and other Alzheimer’s-like symptoms with age. He found that in mouse lemurs, the region is loaded with short stretches of DNA called Alus. If the Alu copies present within the TOMM40 gene interfere with the path from gene to protein, Larsen reasoned, they could help explain why mitochondria in nerve cells stop working.
“Alu elements are a double-edged sword,” Larsen explained. “They have helped humans evolve higher cognitive function, but perhaps at the cost of neuron vulnerability that increases with age.” Alus are normally held in check by clusters of atoms called methyl groups that stick to the outside of the DNA and shut off their ability to jump or turn genes on or off. But in aging brains, DNA methylation patterns change, which allows some Alu copies to reawaken, Larsen said.
The TOMM40 gene encodes a barrel-shaped protein in the outer membrane of mitochondria that forms a channel for molecules—including the precursor to amyloid—to enter. Larsen used 3D modeling to show that Alu insertions within the TOMM40 gene could make the channel protein it encodes fold into the wrong shape, causing the mitochondria’s import machinery to clog and stop working.
Such processes likely get underway before amyloid builds up, so they could point to new or repurposed drugs for earlier intervention, said study co-author Michael Lutz, assistant professor of neurology at Duke.
TOMM40 is one example, the researchers say, but if Alus disrupt other mitochondrial genes, the same basic mechanism could help explain the initial stages of other neurodegenerative diseases too, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS).
The researchers describe the Alu neurodegeneration hypothesis in a paper published online by Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. This study is available at https://dx.doi.org/10.1016/j.jalz.2017.01.017.
“We need to start thinking outside of the box when it comes to treating neurological diseases like Alzheimer’s,” said Larsen, who has filed a provisional patent that focuses on preserving mitochondrial function by keeping Alus in check.
