Biomarkers found in CSF appear capable of identifying the development of Alzheimer disease (AD) years before the onset of symptoms in some people, according to a paper in the August Archives of Neurology. One biomarker, amyloid-beta protein 1-42, (Abeta 42) declines in the CSF of people developing AD as the brain sequesters the soluble oligomers into insoluble plaques. The other, hyperphosphorylated tau, increases.
These biomarkers, combined with evidence of disease provided by neuroimaging, could provide new life for old treatments that have failed to improve cognitive status, possibly because they were administered too late in the disease process, according to John Trojanowski, MD, PhD, one of the authors of the paper.
“Since several treatments tested in clinical trials have succeeded in clearing Abeta 42 from the brain and spinal fluid of people with Alzheimer disease, but have failed to improve their cognitive status, there are concerns that these compounds may not work at the stage of mild AD,” said Dr. Trojanowski, William Maul Measey-Truman G. Schnabel, Jr., MD Professor of Geriatric Medicine and Gerontology, and professor in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine.
The biomarker analysis he and his colleagues have developed may allow pre-symptomatic people with AD to be included in future trials. “That way we could determine if early treatment postpones or even prevents AD,” said Dr. Trojanowski, who is director of the Institute on Aging, the Alzheimer's Disease Core Center, the Udall Parkinson's Research Center, and co-director of the Center for Neurodegenerative Disease Research and the Marian S. Ware Alzheimer Drug Discovery Program.
The study found that combining three biomarkers — CSF levels of Abeta 42, phosphorylated tau, and total tau protein — could identify with 90 percent accuracy which of the 416 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) had been diagnosed with Alzheimer disease. The study also found the biomarkers in 72 percent of those diagnosed with cognitive impairment, and 36 percent of health controls. (The healthy controls were nearly seven times more likely to carry at least one allele of the apolipoprotein E4 gene.)
“The unexpected presence of the Alzheimer's signature in more than a third of cognitively normal subjects suggests that Alzheimer's disease pathology is active and detectable earlier than has heretofore been envisioned,” the authors stated.
The results were validated in two other data sets. In one, 64 of 68 patients (94 percent) with an autopsy-confirmed diagnosis of AD were identified by the biomarkers. In the other, the biomarkers were found in all 57 patients with MCI who progressed to Alzheimer within five years.
Another Archives of Neurology article published online Aug. 9, found that high baseline levels of Abeta 42 in the blood followed by a decline in those levels over time predicted faster cognitive decline in older adults free of dementia.
For nearly five years the authors monitored 880 Medicare recipients in the Washington Heights and Inwood Columbia Aging Project in New York City. Of those, 481 remained cognitively healthy, while 70 developed AD. The remainder were somewhat cognitively or functionally impaired at some point during the study, but not demented.
Those with the highest levels of Abeta 40 and 42 at the start of the study followed by a decline in Abeta 42 over time displayed faster cognitive decline than those in the bottom quartile. However, change in levels of Abeta 40 did not predict change in cognitive status, supporting the widespread belief that Abeta 42 is the toxic oligomer in AD.
With further validation, a blood test for Abeta levels “may be a relatively non-invasive and inexpensive way to identify individuals early in life who are at greater risk for developing Alzheimer disease or rapid cognitive decline,” said study co-author, Stephanie A. Cosentino, PhD, assistant professor of neuropsychology at Columbia University's Taub Institute for Research in Alzheimer's Disease and the Aging Brain.
These two papers “have great significance,” according to veteran Harvard AD researcher Dennis J. Selkoe, MD, a scientific founder of Elan Pharmaceuticals, which has participated in developing various anti-amyloid vaccines. Dr. Selkoe was not involved with the current studies.
“Dr. Trojanowski's paper does a very nice job of confirming an impression that the Alzheimer's research field has had for last decade — that low Abeta 42 levels and elevated tau levels in the spinal fluid comprise a strong indicator that a person is on the way to developing Alzheimer disease,” said Dr. Selkoe, the Vincent and Stella Coates Professor of Neurologic Diseases at Harvard Medical School, and co-director of the Center for Neurologic Diseases. “The other paper [by Mayeux, et al] shows the promise of measuring Abeta 42 levels in the blood, which would be a highly desirable way to test for the risk of developing Alzheimer disease.”
Neurologists have long suspected that the disease begins years if not decades before overt symptoms appear. The prevailing hypothesis holds that toxic Abeta 42 oligomers cut from amyloid precursor protein (APP) by beta- and gamma-secretase enzymes, float in brain and spinal fluid, disrupting synaptic transmissions and promoting damage to the microtubules in the axons that transport many key proteins from the cell body to the synapse. Researchers and drug companies have developed four basic ways to combat this process: vaccines that spur the body's own immune system to clear toxic Abeta 42, monoclonal antibodies that also help clear Abeta 42 and neutralize Abeta oligomers, anti-aggregation agents that reduce the insoluble amyloid plaques in the brain, and secretase inhibitors designed to slow the production of Abeta 42 in the first place.
Clinical trials of such compounds have succeeded in lowering levels of Abeta 42, sometimes dramatically, but have not always slowed cognitive decline. For example, AN1792, an anti-amyloid vaccine developed by Elan Pharmaceuticals, actually eliminated most amyloid plaque in some AD patients, but two treated patients still developed dementia, according to a 2008 paper in The Lancet.
Bapineuzumab, a monoclonal antibody against Abeta, shrank plaques by 25 percent but had no effect on cognition, according to a February report in the Lancet Neurology.
DR. JOHN Q. TROJANOWSKI:“The unexpected presence of the Alzheimer's signature in more than a third of cognitively normal subjects suggests that Alzheimer's disease pathology is active and detectable earlier than has heretofore been envisioned.”
And in 2008 Myriad Genetics abandoned development of tarenflurbil (Flurizan), a gamma-secretase inhibitor, after the largest phase 3 AD trial ever conducted, involving nearly 1,700 people, failed to produce significant cognitive improvement despite the drug's demonstrated ability to reduce brain levels of Abeta. (Efficacy shown in phase 2 trials was reported in 2008 in The Lancet Neurology.)
Development of another gamma-secretase inhibitor known as semagacestat, was halted in August when preliminary results of an ongoing phase 3 study showed that the drug failed to slow disease progression among more than 2,600 patients with mild to moderate AD, and actually worsened their cognitive decline and ability to perform activities of daily living. In addition, semagacestat was associated with an increased risk of skin cancer.
Such failures leave a provocative question hanging in the air: Would these compounds prevent dementia if administered well before overt symptoms of AD appear?
“We are currently trying therapies, particularly anti-amyloid therapies, much too late in the disease process,” said Reisa Sperling, MD, associate 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 in Boston. “I think they have a much better shot at making an impact if we were starting them a decade earlier. Both animal studies and recent disappointing clinical trials suggest that if you wait to intervene until there's already extensive neuronal damage, these therapies don't have much of an impact.”
Dr. Sperling is a member of the workgroup created by the National Institute on Aging and the Alzheimer's Association, which recently developed criteria for “preclinical” Alzheimer disease, a new diagnostic category that precedes mild cognitive impairment and full-blown AD. By combining neuroimaging evidence with biomarkers in CSF and blood, researchers hope to distinguish those who have preclinical AD from those who do not. Clinical trials that included people in the preclinical stage of the disease could help determine if new treatments administered early could postpone or even prevent AD.
“We want to get to the point where we can predict their risk of progression, and then start therapy to see if we can change that risk,” said Dr. Sperling.
This raises ethical issues, since treatments for AD are unlikely to be benign, several independent experts commented. “If someone said, we have a drug that gets rid of amyloid, but 40 percent of the people who take it develop cancer, then you would do a lot of soul searching,” said Marsel Mesulam, MD, Ruth and Evelyn Dunbar Professor of Neurology and Psychiatry, and Psychology, and director of The Cognitive Neurology and Alzheimer's Disease Center at the Northwestern University Feinberg School of Medicine. “You really want to make sure you have a biomarker that identifies not just a substance, but actual dementia. Who would want to take a big risk to get rid of amyloid if the amyloid might not cause the disease?”
Said Brad Dickerson, MD, associate professor of neurology at Harvard Medical School: “The problem is that a large proportion of individuals die with the pathology of Alzheimer disease in their brains, but do not have dementia.”
“We desperately need more studies of the natural history of this process starting with individuals who are cognitively intact who have evidence of AD in their brains to find out which of them develop dementia, how long it takes to develop, and what factors may be associated with more rapid development of dementia, said Dr. Dickerson, director of the Frontotemporal Dementia Unit and Laboratory of Neuroimaging at Massachusetts General Hospital, and co-director of the Neuroimaging Group, Gerontology Research Unit & Alzheimer's Disease Research Center.
DR. REISA SPERLING: “We are currently trying therapies, particularly anti-amyloid therapies, much too late in the disease process. I think they have a much better shot at making an impact if we were starting them a decade earlier.”
Two new papers report on the promise of biomarkers for detecting Alzheimer disease (AD). One paper found that amyloid-beta protein 1-42, (Abeta 42) declines in the CSF of people developing AD as the brain sequesters the soluble oligomers into insoluble plaques, and hyperphosphorylated tau increases. The other found that high baseline levels of Abeta 42 in the blood followed by a decline in those levels over time predicted faster cognitive decline in older adults free of dementia.
Cosentino SA, Stern Y, Mayeux RP, et al. Plasma beta-amyloid and cognitive decline. 2010; E-pub 2010 Aug. 9.
De Myer G, Shapiro F, Trojanowski JQ, et al, for the Alzheimer's Disease Neuroimaging Initiative. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. 2010;67(8):949-956.
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Wilcock GK, Black SE, Laughlin MA, et al, for the Tarenflurbil Phase II Study Investigators. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: A randomised phase II trial. 2008;7(6):483-493.