July 18, 2019
The global race to create an inexpensive and accessible blood test for Alzheimer disease (AD) is heating up. Experts project that such a test could be available in just a few years.
One contender in the race to create such a test is a team led by Akinori Nakamura, MD, PhD, National Center for Geriatrics and Gerontology, Obu, Japan. This group has described a high-performance plasma biomarker that reliably predicts individual brain status of amyloid-beta (Aβ) burden.
In a new study, this plasma biomarker was able to detect early stages of Aβ deposition before patients became symptomatic. Results from use of the test appeared to correlate with evidence of AD on brain imaging.
"Although we still need further validation studies, these results suggest that the plasma biomarker may be useful in screening people who are at risk for Alzheimer's disease," said Nakamura. "This can facilitate clinical trials for Alzheimer's therapies and also accelerate studies to investigate the effects of nondrug interventions, risk management, and lifestyle on Alzheimer's disease."
The findings were presented here at the Alzheimer's Association International Conference (AAIC) 2019.
High Correlation With Gold-Standard Testing
The technology used by these investigators measures plasma levels of amyloid-related peptides (Aβ1-41, Aβ1-40, and AP669-711). The biomarker is generated by combining the ratios of the peptides (APP669-711/Aβ1-42 and Aβ1-40/Aβ1-42).
The investigators compared results from the use of the plasma biomarker to results from brain amyloid positron-emission tomography (PET) scanning, used to assess Aβ deposition; structural MRI, used to assess brain atrophy; fluorodeoxyglucose-PET (FDG-PET) scanning, used to determine glucose hypometabolism; and the Mini–Mental State Examination (MMSE), used to assess cognitive decline.
The study included 201 participants (mean age, 73 years) from three institutes in Japan. The sample included 70 persons who were cognitively normal; 46 who had mild cognitive impairment; 61 who had AD; and 24 who had a non-AD dementia disorder.
Researchers differentiated the samples with respect to high or low Aβ burden in a blinded manner using a standardized uptake value ratio of 1.4 as a cutoff, as well as by visual interpretation by a consensus of experts.
The analysis showed that the biomarker performed well with respect to sensitivity, specificity, and accuracy. Increased specificity was mainly evident in the cognitively normal group, suggesting the biomarker may be able to detect early Aβ deposition.
Biomarker values were significantly correlated with amyloid PET values (P < .001) and results on MRI (P < .001), FDG-PET (P < .002), and MMSE (P < .001).
Commenting on this study for Medscape Medical News, Maria C. Carrillo, PhD, chief science officer, Alzheimer's Association, described the findings as "very exciting."
She noted that the test "correlated very highly" with the "gold-standard" PET amyloid scan as well as with MRI, FDG-PET, and MMSE.
She said the challenge lies in making the test generalizable for "mass marketing purposes."
She also noted that for researchers, having a blood test that can reliably detect AD could help to identify the most appropriate candidates for a clinical trial "more cheaply and more quickly" than is currently possible.
Also commenting on this study, Howard Fillit, MD, founding executive director and chief science officer, Alzheimer's Drug Discovery Foundation, noted the "relatively small sample" in this study.
"For validation, we like to see 500 or 1000 people being studied, and here there's 201 in the sample," he said.
The researchers used mass spectrometry for their assay, which is "fairly sensitive" to Aβ levels in blood, noted Fillit.
There's now "good science" behind blood-based biomarkers for Aβ, and the Japanese team's test is not the only one being developed, said Fillit.
He predicted that a blood test for Aβ could be on the market within 3 to 4 years, "which would be amazing."
The cost of such a blood test may be about $150 and would be covered by insurance. By contrast, the cost of a PET scan can be $5000, which a patient may need to pay out of pocket, he said.
Fillet said that a blood test would not only be useful for clinical trials but also for care planning.
AD is associated with pathologies other than those related to amyloid and tau. One of these is alpha-synuclein (α-syn), a major constituent of Lewy bodies, the presence of which is a hallmark of Parkinson disease and dementia with Lewy bodies.
Another contender in the race for a plasma AD biomarker is a test that analyzes concentrations of α-syn and its heterocomplexes of proteins that are misfolded and combined together molecularly, for example, α-syn plus Aβ and α-syn plus tau in red blood cells (RBCs).
Investigators from the University of Pisa, Italy, analyzed these concentrations in 39 AD patients who had either dementia or prodromal symptoms and in 39 age-matched healthy control persons. For all case patients, MMSE scores were higher than 20 points.
The AD patients had received a biomarker-based diagnosis. This meant their cerebrospinal fluid levels of Aβ peptide were low and a cerebrospinal PET scan indicated high amyloid levels.
The study results, which were presented at the AAIC 2019, showed much lower concentrations of α-syn and its heterocomplexes in RBCs of AD patients compared to control persons.
RBC α-syn/Aβ and α-syn/tau enabled the researchers to distinguish patients who had AD from healthy control persons with "fair accuracy" of 70% to 80%, study investigator Filippo Baldacci, MD, Department of Clinical and Experimental Medicine, told Medscape Medical News.
Although additional research is needed, "this could be a feasible and reliable screening tool for AD in the future," said Baldacci.
Use of such a screening tool could be the first step toward making a firm diagnosis of AD, he added.
An Exciting First
This prospective AD blood test is also "super exciting," although the study included a small sample, said Carrillo.
"This is the very first time that we have seen anyone be able to detect alpha-synuclein in a living human being, not at autopsy; that's a big deal for the field," she said.
Researchers have known for some time that AD involves pathologies other than just amyloid and tau, said Carrillo. "In AD brains at autopsy, you might have three or four or five different pathologies all combining," and alpha-synuclein could be among those, she said.
These results "portend the future, which is the ability to tell in life all the different possible brain changes that are associated with neurodegeneration, and potentially be able to treat them," Carrillo added.
Like the previous study, this one is also exploratory, said Fillet.
"The findings are not as robust as we would like; the correlation coefficients aren't that high," he noted. However, he said, in general, this area of research "is interesting and a road we have to go down," because α-syn is among the pathologies linked to AD.
"This test could be potentially helpful for differential diagnoses of people with dementia, depending on amounts of alpha-synuclein or these ratios of alpha-synuclein, but it's very exploratory," he said.
Nakamura, Baldacci, Carrillo, and Fillit have disclosed no relevant financial relationships.
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