ICAD: Biomarkers May Help Identify Pre-Clinical Alzheimer's

By Todd Neale
CHICAGO, 31 july 2008-- Several biomarkers may be useful in detecting the pre-clinical stages of Alzheimer's disease or in evaluating the effectiveness of therapies in development, researchers said here.
Four studies presented at the International Conference on Alzheimer's Disease explored the usefulness of biomarkers in blood and cerebrospinal fluid and a new tracer for positron emission tomography (PET).
"There's been a focus on moving the detection threshold for this disease into earlier symptomatic phases and ultimately into asymptomatic individuals," said Ronald Petersen, M.D., Ph.D., of the Mayo Clinic in Rochester, Minn., and vice chair of the medical and scientific advisory council of the Alzheimer's Association, who moderated the session at which the results were presented.
Biomarkers are needed to do the latter, Dr. Petersen said.
"It is greatly preferable that these markers be easy to obtain, such as in samples of blood or urine, or through readily available imaging technologies, such as MRI and PET," said William Thies, Ph.D., vice president of medical and scientific relations at the association.
One such biomarker -- increased expression of the protein CD-69 in peripheral blood lymphocytes -- was identified by researchers at the University of Leipzig in Germany.
Measuring the expression of CD-69 differentiated patients who were diagnosed with Alzheimer's from patients with normal cognitive function with 88% and 82% accuracy, respectively, said Louis Kirby, M.D., chief medical officer for Provista Life Sciences, which oversees the company that licensed the assay, called the LymPro test.
It also differentiated those who were diagnosed with Alzheimer's from demented Parkinson's patients with 91% accuracy when the diagnosis was Alzheimer's and 92% accuracy when the diagnosis was Parkinson's.
A larger trial is underway to verify the results, Dr. Kirby said, and the test could be on the market in October.
Two other studies explored biomarkers in cerebrospinal fluid.
The first, presented by Anne Fagan, Ph.D., of Washington University in St. Louis, looked at beta-amyloid42, a form of the protein that is particularly likely to create plaques characteristic of Alzheimer's disease.
In an earlier small study, Dr. Fagan and her colleagues had shown that the level of beta-amyloid42 in cerebrospinal fluid was inversely associated with plaques in the brain, as measured with PET scans using Pittsburgh Compound B (11C-PIB) as a tracer. (See: Another Avenue for Detecting Early Alzheimer's)
The researchers repeated the study in a larger cohort of 132 patients (mean age 65.7) who had no to mild dementia, and found similar results.
Of 37 patients who had a large amount of plaques, 36 (97%) had low levels of beta-amyloid42.
Of 95 patients with low levels of plaques, 80 (84%) had high levels of the protein in their cerebrospinal fluid.
"Our analyses suggest that a decline in [beta-amyloid42 in cerebrospinal fluid] may effectively identify non-demented individuals who are in the preclinical stage of Alzheimer's, even before they are PIB positive," Dr. Fagan said.
The second study examined the presence of another protein, beta-secretase (BACE1), in cerebrospinal fluid.
Past studies have shown that the protein is involved in the processing of amyloid precursor protein and the production of toxic beta-amyloid, and that it is over-expressed in the brains of Alzheimer's patients.
So Harald Hampel, M.D., of Trinity College Dublin, and colleagues examined the presence of BACE1 in the cerebrospinal fluid of 47 patients with mild cognitive impairment.
After a mean of 2.3 years of follow-up, 15 of the patients had developed Alzheimer's disease.
Cox-regression analysis showed that BACE1 levels and APOE e4 genotype -- a risk factor for Alzheimer's disease -- were the strongest predictors for progression to Alzheimer's.
The technique requires further study, Dr. Hampel said, but it may eventually be used as an outcome biomarker in clinical trials of anti-amyloid therapies for Alzheimer's.
A fourth study evaluated the effectiveness of a new tracer for PET scans of amyloid plaques.
The first tracer developed, 11C-PIB, has a relatively short half-life -- 20 minutes -- making it suited mostly for larger medical centers that can produce the compound on-site.
Michael Pontecorvo, Ph.D., of Avid Radiopharmaceuticals in Philadelphia, reported that a new tracer, called 18F-AV-45, has a longer half-life -- about two hours -- and therefore, would not necessarily have to be made on-site.
The tracer was retained in the brains of patients diagnosed with Alzheimer's but not in older individuals with normal cognitive function and showed rapid uptake and steady levels in the brain from 50 to 90 minutes after administration.
The compound "has the potential to aid in the diagnosis and early detection of Alzheimer's in a community setting and may be a useful biomarker for the development and monitoring of novel amyloid reducing therapies," Dr. Pontecorvo said.
Phase II trials with the compound have been initiated, he said.
Dr. Fagan's study was supported by grants from the NIH and the National Institute on Aging and by the Dana Foundation and the Charles and Joanne Knight Alzheimer's Initiative.
Dr. Hampel made no disclosures.
Dr. Pontecorvo is an employee of Avid Radiopharmaceuticals.
Dr. Petersen has participated in previous studies with Avid.