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AD Prevention Trial Moves Forward
The Opportunities and the Risks



DR. RANDALL BATEMAN: “This is a rare opportunity to treat people before they manifest symptoms of the disease. It could have major medical and scientific impact as well as a more personal impact for the patients and their families.”

Investigators describe the longitudinal trial that will assess the ability of three drugs to abet and prevent Alzheimer's disease in asymptomatic people with known mutations for the disease.

The Oct. 10 announcement about plans for an Alzheimer's disease prevention trial — assessing how three different drugs attack amyloid beta (Abeta) in people around the world who have an autosomal-dominant mutation for Alzheimer's disease (AD) — has elicited great hope and some trepidation among leading AD investigators. On one hand, clinicians and researchers alike are hoping that earlier treatment could abet or at least slow the progression of the disease. On the other hand, some investigators worry about the risks associated with exposing asymptomatic people to potentially toxic drugs.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN TU) — based at Washington University in St. Louis — is scheduled to start next year. It will include 240 participants total, 160 of whom carry an AD mutation, said Randall Bateman, MD, the Charles F. and Joanne Knight distinguished professor of neurology at Washington University School of Medicine.

“This is a rare opportunity to treat people before they manifest symptoms of the disease,” said Dr. Bateman. “It could have major medical and scientific impact as well as a more personal impact for the patients and their families.”


The drugs chosen for the trial include gantenerumab, made by Roche Neurosciences, and solanezumab manufactured by Eli Lilly — both humanized monoclonal antibodies, which bind to different amyloid protein structures inside the brain. The third drug being considered is a beta-secretase (BACE) inhibitor that attempts to prevent Abeta from forming. Only those who have the mutation for AD will receive the medications.

Roche and Lilly have agreed to make the treatments available at no cost and will help support the trial, as will the Alzheimer's Association.

The trial committee considered 15 different drugs — submitted by 10 different companies. “We chose drugs that are likely to impact the underlying disease process,” said Dr. Bateman. “These drugs have a safety and efficacy profile that supports their potential for success.”

The goal is to attack Abeta, a protein that forms and deposits in the brain as a form of plaque. The first phase of the trial will assess whether one or more of the three drugs can halt or reverse pathological changes in the preclinical biomarkers known to be present in the trial participants. In the second phase, investigators will determine whether these changes effectively halt disease process and symptoms. The trial aims to start treating participants long before — using a 15-year window — the symptoms of the disease show.

“That's about the time when changes in amyloid begin to develop,” said Dr. Bateman.


Some neurologists expressed concerns about potential side effects of the drugs, however. Rachelle S. Doody, MD, PhD, professor of neurology and the Effie Marie Cain Chair in Alzheimer's Disease Research and director at the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine, agrees that interventions should be offered to those who carry AD mutations, and said that each experimental therapy should be considered in terms of its risk to benefit ratio, which shifts depending on the population and the drug.

The risks for solanezumab seem to be low, said Dr. Doody, who reported on the Alzheimer's Disease Cooperative Study analysis of clinical data from two Eli Lilly-sponsored studies of the drug, EXPEDITION 1 and EXPEDITION 2 at the American Neurological Association annual meeting in October. [See Neurology Today's “Anti-Beta Amyloid Drug Modestly Slows Cognitive Decline in Mild to Moderate AD”;] There was a less than 1 percent incidence of vasogenic edema, compared with half of a percent for those taking the placebo, she said. Although there might be a signal of side effects related to cardiac disorders — 1.1 percent of patients taking solanezumab had angina vs. 0.2 percent of those on placebo — no clear pattern emerged in two large phase 3 studies of over 2,000 people, she pointed out.

Gantenerumab is in phase 2 testing [in the Study of Gantenerumab in Patients With Prodromal Alzheimer's Disease], and its potential side effects are less well understood since fewer patients have been exposed and there is less information in the public domain or through peer-reviewed papers, Dr. Doody said. There have been some presentations that indicate the incidence of vasogenic edema, with or without brain hemorrhage, may be higher than with solanezumab.

But even less is known about the BACE inhibitor. “It's in the early phase of trials and animal studies using drugs with similar mechanisms show that they might affect myelin, the insulator found around the projections,” Dr. Doody said. [For more on the trial, see “Study of LY2886721 in Mild Cognitive Impairment Due to Alzheimer's Disease or Mild Alzheimer's Disease,”] “There were also some reports that such drugs could damage the retina of the eye in animals.” Because of these concerns, she suspects that the DIAN investigators will await more human data before deciding to proceed with the BACE inhibitor.

Dr. Bateman said that although the BACE inhibitor was in the early phase 2 level of clinical development with little published data — those involved in the trial were enthusiastic about the mechanism of the drug because it targets and blocks the production of amyloid.


DR. RACHELLE S. DOODY agrees that interventions should be offered to those who carry Alzheimers disease mutations, but said that each experimental therapy should be considered in terms of its risk to benefit ratio, which shifts depending on the population and the drug.

Reisa Sperling, MD, professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital and Massachusetts General Hospital Memory Disorders Unit, said the BACE inhibitor was “definitely in an earlier development phase” but that researchers have high hopes that it could reduce the production of amyloid development.


DR. DAVID S. KNOPMAN: “This trial is on the edge, theres no question about it. Theyre trying to do something in a preclinical space thats never been done before.”

With any study involving monoclonal antibodies, there is a risk for amyloid-related imaging abnormalities, or microhemorrhages, she said, adding that researchers regularly screen for those problems.

“For the BACE inhibitor, it's much less clear what the risks are going to be yet,” she said.

A majority of those in the DIAN study will start receiving the medications in their 30s, 40s, and 50s, assuming targets for individuals 15 years before symptom onset.

Given that this estimate could be off by five years or so, Dr. Doody pointed out that the risk-benefit ratio argues for special caution in people who are much younger than their estimated age of onset. “They could live 20 years completely symptom free so an intervention with morbidity could really alter their life course.”

Dr. Bateman said the drugs will be given on average within a few years of symptom or cognitive decline onset. So there is not a predicted scenario where someone would be on the drug for 30 years (or even 20).

“Participants and family members have been the most vocal about requesting drugs which may have an impact, even with the potential for some side-effects,” said Dr. Bateman. “We meet with them every four to five months and review the plans for trials, the potential for side effects and the design of the study. The participants have had a major role in the design of the DIAN TU trial.”

And what do you tell patients about the potential risks? David S. Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN, said that there are risks to the trial, but that if he had a relative with the genetic mutation for Alzheimer's, he would encourage them to be part of the study.

“This trial is on the edge, there's no question about it,” Dr. Knopman said. “They're trying to do something in a preclinical space that's never been done before.”

“There is a real ethical argument that there should be more leeway,” in the risk-benefit ratio with this trial, he said. “Is it the right choice? I don't know. Is it a reasonable choice? Yes.”


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      • Bohrmann B, Baumann K, Loetscher H, et al. Gantenerumab: A novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis 2012;28(1):49–69.
        • Farlow M, Arnold SE, Siemers ER, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimers Dement 2012;8(4):261–71. E-pub 2012 Jun 5.
          • Lachno DR, Emerson JK, Dean RA, et al. Validation of a multiplex assay for simultaneous quantification of amyloid- peptide species in human plasma with utility for measurements in studies of Alzheimer's disease therapeutics. J Alzheimers Dis 2012. E-pub 2012 Aug 9.
            Neurology Today archive on Alzheimer's disease:
              • DIAN Study website: