Promising New Targets Identified in Early AD
Promising New Targets Identified in Early AD
A soluble amyloid-β (Aβ) oligomer labeled Aβ*56 that's so tiny it's invisible even under a microscope but can be diffuse throughout the brain may be a more promising target than amyloid plaque for future drug trials in Alzheimer's disease (AD), a new study suggests.
Researchers report that this oligomer, along with a second one, Aβ trimers, correlated with tau in cognitively normal older adults but that the correlation weakened in adults with symptoms of AD. They also found that another cerebrospinal fluid (CSF) biomarker, Aβ1-42, which is a surrogate for amyloid plaque, had no relationship with tau.
"The correlation between these Aβ oligomers and tau was surprisingly strong," said study author Karen H. Ashe, MD, PhD, director, N. Bud Grossman Center for Memory Research and Care, and professor of neurology, University of Minnesota Medical School, Minneapolis.
"One of the conclusions of the study may be that there's strong coupling between Aβ*56 and trimers with tau in the asymptomatic phase of the disease but not the symptomatic phase, and this may explain why it's important to treat in the asymptomatic phase of the disease. If one does treat in the asymptomatic phase, one or both of these oligomers may be more important to target than amyloid plaques."
Determining which Aβ species to target in asymptomatic persons may enhance the success of future drug development, said Dr. Ashe.
The study was published online March 11 in JAMA Neurology.
Surprisingly Strong Relationship
Researchers obtained CSF samples from 48 older adults with mild cognitive impairment (MCI) or AD, who made up the "impaired" group; from 49 age-matched cognitively intact controls, who made up the "unimpaired" group; and from 10 younger, normal controls.
The study found that levels of Aβ*56 and Aβ trimers increased with age in cognitively normal persons and in persons who were at greater risk for AD.
The researchers found a strong positive relationship between the Aβ oligomers, but not Aβ1-42, and tau in cognitively normal older adults. This relationship was attenuated in MCI and AD.
These new findings suggest that in the years before onset of overt AD symptoms, 1 or both of the Aβ oligomers but not fibrillar Aβ is coupled to tau, and that this coupling is weakened or broken when AD advances to symptomatic stages, according to the authors.
In the past, drug research has focused on the amyloid plaques because plaques and tangles are the most prominent neuropathologic features in the clinical symptomatic phase of the disease, said Dr. Ashe.
She noted research that goes back 10 or more years that found cognitively normal people who had high levels of tau in CSF were more likely to develop AD over time.
The uncoupling of Aβ oligomers and tau in MCI/AD that the study uncovered may help explain why experimental Aβ therapies have consistently failed to alter the clinical course of patients with MCI or AD.
"It's believed that one of the reasons these therapies have failed is that the Aβ in the plaques and the tau in the tangles may have become uncoupled by the time the treatment has begun," said Dr. Ashe.
Plaques are very tiny and occupy only a very small fraction of the brain, she said. "It may be the case that if you target the plaques, you're only going to improve the brain function in the small regions of the brain that they occupy, but if you can target Aβ*56, because it's diffuse, you may be able to affect a far greater region of the brain."
Match Lighting Fuse
The research underlines the importance of the biological link between tau and Aβ, she said. A person can high levels of tau and Aβ, but these must be linked to set in motion the disease that becomes AD. Using a dynamite analogy, Dr. Ashe likened Aβ to the match and tau the fuse — when they link together at a molecular level, it sets in motion the spreading destruction of surrounding neurons.
The failure of therapies initiated after symptoms appear has prompted a shift in the timing of Aβ therapies to asymptomatic persons. But this new study suggests that drugs might be most effective if they target Aβ*56 or Aβ timers in this earlier phase, before symptoms appear, said Dr. Ashe.
And Aβ*56 might be a better target than Aβ trimers, according to results of another study by Dr. Ashe's research team that is now in press.
"We found that in the actual brain tissue, not in the spinal fluid, Aβ*56 correlates with tau, but Aβ trimers does not, in cognitively intact older adults," she said.
As well as being an important therapeutic target, Aβ*56 may be an interesting marker to monitor drug effects, said Dr. Ashe.
Her team is testing drugs that target Aβ*56 and other forms of Aβ in mice. "We're trying to see if we can obtain appropriate changes in brain function, and hopefully some day we can look for changes in tau in spinal fluid as well, and determine if these treatments that target Aβ*56 are effective."
Working with animal models of AD is a challenge, though; AD is a disease that takes such a long time to manifest in humans that some animal research may not be relevant, said Dr. Ashe. "It may not be possible to extrapolate results that take place in cells over a few days or weeks or in mice that live a few years to something that takes place over 2 decades in humans."
Toxic Beast
Invited to comment on these new developments, Ron Petersen, MD, PhD, director, Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minnesota, said that Dr. Ashe "may be on to something." She has been working on this concept for several years, he noted, that these oligomers are precursors of the fibrillar form of Aβ that eventually make up plaques.
Her study, said Dr. Petersen, suggests that these oligomers are "the toxic beast." The implications of this research are that "we should attack the embryonic form of amyloid plaques because those are the ones that are causing the damage, and that this form may be treatable if we can, for example, get an antibody or something to get the oligomeric form before the plaque is made."
However, the problem with this approach is that the current focus is very much on developing biomarkers for plaque, said Dr. Petersen. "A lot of our technology these days is aimed at picking up the plaques using PET [positron emission tomography] imaging."
He pointed out that although clinical trials of solanezumab (Eli Lilly), a monoclonal antibody that binds to soluble forms of amyloid-β before it clumps together to form plaques, were generally negative for improvement in measures of cognitive and functional status in patients with mild to moderate AD, evidence suggested that the biomarker did engage the target in patients with mild disease.
"That means that they did engage the plaque with the antibody, although Dr. Ashe would say, 'so what? It's still too late'," Dr. Petersen said. Dr. Ashe "is a creative thinker" and well respected in the field, he added. "She just may be right."
Dr. Ashe and Dr. Petersen have disclosed no relevant financial relationships.
JAMA Neurol. Published online March 11, 2013. Abstract
A soluble amyloid-β (Aβ) oligomer labeled Aβ*56 that's so tiny it's invisible even under a microscope but can be diffuse throughout the brain may be a more promising target than amyloid plaque for future drug trials in Alzheimer's disease (AD), a new study suggests.
Researchers report that this oligomer, along with a second one, Aβ trimers, correlated with tau in cognitively normal older adults but that the correlation weakened in adults with symptoms of AD. They also found that another cerebrospinal fluid (CSF) biomarker, Aβ1-42, which is a surrogate for amyloid plaque, had no relationship with tau.
"The correlation between these Aβ oligomers and tau was surprisingly strong," said study author Karen H. Ashe, MD, PhD, director, N. Bud Grossman Center for Memory Research and Care, and professor of neurology, University of Minnesota Medical School, Minneapolis.
"One of the conclusions of the study may be that there's strong coupling between Aβ*56 and trimers with tau in the asymptomatic phase of the disease but not the symptomatic phase, and this may explain why it's important to treat in the asymptomatic phase of the disease. If one does treat in the asymptomatic phase, one or both of these oligomers may be more important to target than amyloid plaques."
Determining which Aβ species to target in asymptomatic persons may enhance the success of future drug development, said Dr. Ashe.
The study was published online March 11 in JAMA Neurology.
Surprisingly Strong Relationship
Researchers obtained CSF samples from 48 older adults with mild cognitive impairment (MCI) or AD, who made up the "impaired" group; from 49 age-matched cognitively intact controls, who made up the "unimpaired" group; and from 10 younger, normal controls.
The study found that levels of Aβ*56 and Aβ trimers increased with age in cognitively normal persons and in persons who were at greater risk for AD.
The researchers found a strong positive relationship between the Aβ oligomers, but not Aβ1-42, and tau in cognitively normal older adults. This relationship was attenuated in MCI and AD.
These new findings suggest that in the years before onset of overt AD symptoms, 1 or both of the Aβ oligomers but not fibrillar Aβ is coupled to tau, and that this coupling is weakened or broken when AD advances to symptomatic stages, according to the authors.
In the past, drug research has focused on the amyloid plaques because plaques and tangles are the most prominent neuropathologic features in the clinical symptomatic phase of the disease, said Dr. Ashe.
She noted research that goes back 10 or more years that found cognitively normal people who had high levels of tau in CSF were more likely to develop AD over time.
The uncoupling of Aβ oligomers and tau in MCI/AD that the study uncovered may help explain why experimental Aβ therapies have consistently failed to alter the clinical course of patients with MCI or AD.
"It's believed that one of the reasons these therapies have failed is that the Aβ in the plaques and the tau in the tangles may have become uncoupled by the time the treatment has begun," said Dr. Ashe.
Plaques are very tiny and occupy only a very small fraction of the brain, she said. "It may be the case that if you target the plaques, you're only going to improve the brain function in the small regions of the brain that they occupy, but if you can target Aβ*56, because it's diffuse, you may be able to affect a far greater region of the brain."
Match Lighting Fuse
The research underlines the importance of the biological link between tau and Aβ, she said. A person can high levels of tau and Aβ, but these must be linked to set in motion the disease that becomes AD. Using a dynamite analogy, Dr. Ashe likened Aβ to the match and tau the fuse — when they link together at a molecular level, it sets in motion the spreading destruction of surrounding neurons.
The failure of therapies initiated after symptoms appear has prompted a shift in the timing of Aβ therapies to asymptomatic persons. But this new study suggests that drugs might be most effective if they target Aβ*56 or Aβ timers in this earlier phase, before symptoms appear, said Dr. Ashe.
And Aβ*56 might be a better target than Aβ trimers, according to results of another study by Dr. Ashe's research team that is now in press.
"We found that in the actual brain tissue, not in the spinal fluid, Aβ*56 correlates with tau, but Aβ trimers does not, in cognitively intact older adults," she said.
As well as being an important therapeutic target, Aβ*56 may be an interesting marker to monitor drug effects, said Dr. Ashe.
Her team is testing drugs that target Aβ*56 and other forms of Aβ in mice. "We're trying to see if we can obtain appropriate changes in brain function, and hopefully some day we can look for changes in tau in spinal fluid as well, and determine if these treatments that target Aβ*56 are effective."
Working with animal models of AD is a challenge, though; AD is a disease that takes such a long time to manifest in humans that some animal research may not be relevant, said Dr. Ashe. "It may not be possible to extrapolate results that take place in cells over a few days or weeks or in mice that live a few years to something that takes place over 2 decades in humans."
Toxic Beast
Invited to comment on these new developments, Ron Petersen, MD, PhD, director, Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minnesota, said that Dr. Ashe "may be on to something." She has been working on this concept for several years, he noted, that these oligomers are precursors of the fibrillar form of Aβ that eventually make up plaques.
Her study, said Dr. Petersen, suggests that these oligomers are "the toxic beast." The implications of this research are that "we should attack the embryonic form of amyloid plaques because those are the ones that are causing the damage, and that this form may be treatable if we can, for example, get an antibody or something to get the oligomeric form before the plaque is made."
However, the problem with this approach is that the current focus is very much on developing biomarkers for plaque, said Dr. Petersen. "A lot of our technology these days is aimed at picking up the plaques using PET [positron emission tomography] imaging."
He pointed out that although clinical trials of solanezumab (Eli Lilly), a monoclonal antibody that binds to soluble forms of amyloid-β before it clumps together to form plaques, were generally negative for improvement in measures of cognitive and functional status in patients with mild to moderate AD, evidence suggested that the biomarker did engage the target in patients with mild disease.
"That means that they did engage the plaque with the antibody, although Dr. Ashe would say, 'so what? It's still too late'," Dr. Petersen said. Dr. Ashe "is a creative thinker" and well respected in the field, he added. "She just may be right."
Dr. Ashe and Dr. Petersen have disclosed no relevant financial relationships.
JAMA Neurol. Published online March 11, 2013. Abstract
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