Alzheimer’s Findings Offer New Direction on Treatment

In separate probes into the roots of Alzheimer’s, scientists have uncovered a rare gene mutation that keeps plaque from forming in the brain and found the disease may take hold 25 years before symptoms appear.

The DNA variant slows production of an enzyme called beta secretase-1 that helps form the hallmark brain tangles. The finding, reported in the journal Nature, supports the validity of drugs being developed by Merck & Co., Eli Lilly & Co. and other companies designed to slow release of the enzyme, said Kari Stefansson, a report author.

The second study, published in the New England Journal of Medicine, involved people with DNA that predisposed them to the disease before age 60. That research found changes in spinal fluid 25 years before symptoms began, and brain volume differences 15 years earlier. Together, the reports may lay groundwork allowing scientists to identify when it may be best to start treating patients and, perhaps, hold off the disease.

“These are steps on the pathway, really high-quality ones,” said William Thies, chief medical and scientific officer for the Chicago-based Alzheimer’s Association. Though the findings won’t lead directly to drugs and diagnostics, they may provide a foundation for them, he said.

More than 5 million Americans have Alzheimer’s, which is the most-common type of dementia, according to the Alzheimer’s Association. Global dementia cases are expected to double within 20 years to as many as 65.7 million people, the Geneva-based World Health Organization said in April.

DIAN Group

The New England Journal study focused on a group called the Dominantly Inherited Alzheimer Network, or DIAN. People in this group have a dominant gene mutation inherited from their parents guaranteeing they’ll get Alzheimer’s and suffer dementia before age 60, said Randall Bateman, a study author and a professor of neurology at Washington University School of Medicine in St. Louis. That makes them an ideal to study the disease’s progress, he said in a telephone interview.

“This may mean there’s a window of opportunity to potentially intervene,” Bateman said. “The symptoms may represent a brain failure after damage has been going on for decades.”

The researchers used the DIAN group to estimate the time to the onsets of symptoms by comparing them with their parents’ data. A 35-year-old whose parent was 45 when the symptoms began was thought to be 10 years away from onset, the report said.

Certain signs, or biomarkers, found in spinal fluid or the brain let scientists track disease progression, said Laurie Ryan, the program director for Alzheimer’s disease clinical trials at the National Institute on Aging in Bethesda, Maryland.

Changes Tracked

The researchers noted when changes occurred and accrued over time, she said. If tests can be developed to determine whether a person is at risk for the disease it may aid diagnosis, help improve treatment and speed drug development, the Alzheimer’s Association’s Thies said.

“Getting to the point where we can do a biomarker endpoint for phase 3 clinical trials, that’s going to take a while,” Thies said. “But we’re on the road to that.”

The first sign of impending Alzheimer’s in the DIAN patients -- found 25 years before the expected beginnings of symptoms -- was a drop in beta amyloid in the cerebrospinal fluid. That indicates the protein isn’t getting cleared out of the brain, Ryan said. While healthy brains break down and eliminate beta amyloid, the protein fragments accumulate and start to clump in the brains of people with Alzheimer’s.

Brain Atrophy

The next changes, observed 15 years before the expected symptomatic illness, showed abnormal deposits of beta amyloid and increased levels of tau, another characteristic Alzheimer’s protein, as well as brain atrophy.

Five years after that, patients start to experience memory problems. About three years after they were expected to have symptom onset, patients meet the diagnostic criteria for dementia, according to the study.

Bateman’s group is planning an extension of the study that looks at three yet-to-be-determined experimental drugs, to see if treating patients earlier will help stave off the effects of the mind-robbing illnesses.

Because the DIAN group uses an early-onset form of the illness, meaning before age 60, Bateman and other scientists urged caution in stretching the finding to the more-common late onset type of Alzheimer’s.

“We don’t know if this is exactly what we’d see in late-onset Alzheimer’s disease,” in the course of the disease in people without the mutation, Ryan said. “But we have data that suggests similar patterns.”

Drug Trials

Drug trials are being planned to evaluate whether earlier intervention will help people who are at added risk for Alzheimer’s due to family history or because they carry certain biomarkers for the disease without showing impairment. Those trials will be discussed at the Alzheimer’s Association International Conference in Vancouver beginning on July 14.

The finding of a rare, gene mutation that protects against Alzheimer’s, described in the paper published in Nature, may support new treatment approaches in fighting the brain plaques associated with the disease. Scientists from deCode Genetics Inc. discovered the mutation that prevents an enzyme called beta secretase 1, or BACE-1, from helping create the characteristic beta amyloid tangles in the brains of Alzheimer’s patients. Drugs that mimic this action are in development from Merck & Co., Eli Lilly & Co. and Eisai Co.

The variant points to a mechanism that’s different from the experimental therapies from Johnson & Johnson, Pfizer Inc. and Lilly that are designed to clear beta amyloid from the brain by binding directly to the protein. The mutation was associated with a 40 percent reduction in beta amyloid in those people carrying it, the paper said.

Clinical Testing

The discovery signals that beta secretase inhibitors such as Merck’s, expected this year to start the second of three phases of clinical testing generally needed for marketing approval, might be on the right track.

“It provides encouraging evidence that reducing the production of amyloid, and in particular through beta secretase activity matters for preclinical disease,” said Eric Reiman, chief executive officer of Banner Research, a Phoenix-based medical research institute, and a professor of psychiatry at the University of Arizona in a telephone interview. “The question is, how early do you need to start?”

Before it's here, it's on the Bloomberg Terminal. LEARN MORE