22 January 2011. For anyone in an Alzheimer’s disease study who is nervous about a spinal tap, the idea of measuring dementia risk with a simple blood test would be a dream come true. This dream has long seemed out of reach. Studies of plasma markers have delivered maddeningly inconsistent results. A paper in the January 19 Journal of the American Medical Association now suggests that a blood test for amyloid-β (Aβ) deserves a closer look. Researchers led by Kristine Yaffe at the University of California in San Francisco took baseline plasma samples from nearly 1,000 elderly normal volunteers and then followed the participants for nine years, regularly measuring their cognitive performance. Unlike similar previous studies, Yaffe and colleagues looked at cognitive decline rather than conversion to AD, perhaps making the results more sensitive. They found that a low ratio of plasma Aβ42 to Aβ40 at baseline correlated with a greater drop in mental abilities over the length of the study. Intriguingly, this association was strongest in participants with low levels of education and literacy, and much weaker in people with more education. This fits with the long-standing view that a person’s cognitive reserve can protect against mental decline. If the result proves robust in future studies, it may re-ignite interest in using blood tests to monitor AD risk.
“The most important message from this and similar studies is that differences in proteins and peptides can be found in peripheral fluids years before clinical onset of dementia. This is good news,” wrote Monique Breteler of University Medical Center Rotterdam, The Netherlands, in an accompanying editorial in JAMA. Breteler points out, however, that to measure up as a biomarker, a protein must be shown to carry a quantifiable disease risk, and that plasma Aβ has a long way to go to meet this standard.
So far in the AD field, cerebrospinal fluid (CSF) biomarkers have dominated the discussion, with low levels of CSF Aβ42 showing a reliable correlation with AD risk (e.g., see ARF related news story). Amyloid in blood, on the other hand, has yielded a more confusing picture. Some studies have found a relationship between low levels of plasma Aβ and development of Alzheimer’s (see ARF related news story on Graff-Radford et al., 2007; Pesaresi et al., 2006; van Oijen et al., 2006; Lewczuk et al., 2010), including one from last year that followed more than 1,000 elderly people in France over four years (see ARF related news story on Lambert et al., 2009). Other work, meanwhile, has shown the opposite pattern, with high levels of plasma Aβ dovetailing with disease risk (see ARF related news story on Schupf et al., 2008; Mayeux et al., 2003). One possible explanation that has been put forth for this discrepancy is that plasma Aβ might be high initially in people at risk for AD, then drop as people approach Alzheimer’s (see Cosentino et al., 2010). This hypothesis does not explain negative results, however: several studies have failed to find any strong association between plasma Aβ and cognition (see ARF related news story on Hansson et al., 2008; Lopez et al., 2008; and Fukumoto et al., 2003).
Part of the problem may lie in the way Aβ is handled, suggested several researchers. “Aβ is difficult to measure,” said Henrik Zetterberg at Sahlgrenska University Hospital in Molndal, Sweden, explaining that the protein not only self-aggregates, but also binds to many other proteins in plasma. “The exact way the assay is performed will influence the results.” To try to minimize this problem, Yaffe and colleagues chose to use the relatively new INNO-BIA assay developed by Innogenetics in Ghent, Belgium, to measure Aβ. This assay was used in the recent French study and is also employed by the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Innogenetics' method is more sensitive than previous techniques, Yaffe said, and appears to deliver consistent results.
The authors also wanted to conduct a large prospective study with extensive follow-up. To that end, Yaffe and colleagues recruited almost 1,000 healthy elderly volunteers living in Tennessee and Pennsylvania; about half were white and half were African-American. The researchers collected blood samples one year into the study, and sent them to the laboratory of Steve and Linda Younkin at the Mayo Clinic in Jacksonville, Florida, for analysis. The results provided baseline values for plasma Aβ that were then divided into tertiles. To monitor cognitive ability, participants took the Modified Mini-Mental State Examination approximately every two years. A low initial ratio of Aβ42/40 was associated with greater cognitive decline over nine years. People in the lowest tertile on average lost more than six points on their exam score, three points more than those in the highest tertile. Adjusting the data for various confounding factors such as age, race, diabetes, smoking, and ApoE genotype made no difference in this result. However, the association between Aβ levels and test scores was weaker in people who had at least a high school diploma and higher than sixth-grade literacy, and stronger in those with less education.
This is one of the most interesting findings from the study, Yaffe said, because it supports the hypothesis of cognitive reserve. Roughly put, the idea is that using your brain more can strengthen it and make it more resistant to neurodegenerative disease. “I think it’s exciting because it implies that even if you have a biomarker [for AD risk], you could do something about it by getting more cognitive stimulation,” Yaffe said. Numerous clinical trials are testing whether mental and physical stimulation can delay the development or progression of cognitive problems or AD (e.g., this cognitive training and exercise trial, cognitive training trial, and computer-based training trial). However, a recent review of cognitive interventions, authored by Mike Martin of the Universität Zurich, Switzerland, and colleagues, found no evidence that trials conducted to date have been effective in improving memory. Martin and colleagues note that it is still possible that longer, more intense, or different interventions might be beneficial (see Martin et al., 2011).
A number of epidemiological studies have shown an association between cognitive reserve and lower dementia risk, but so far only a few have tied this interaction to biomarkers. Two recent papers found that in highly educated people, a heavy brain amyloid load as revealed by positron emission tomography with Pittsburgh Compound B (PIB) was less predictive of mental decline (see Kemppainen et al., 2008; Rentz et al., 2010). Dorene Rentz of Massachusetts General Hospital, Boston, presented new data on this issue at the 2010 Human Amyloid Imaging meeting (stay tuned for upcoming news story), and is enthusiastic about the work by Yaffe and colleagues.
“I think the take-home message is that cognitive reserve does provide a protective performance effect in the earliest stages of the disease and may mask evidence of pathology,” Rentz wrote in an e-mail to ARF, adding, “The strength and value of this study is its nine-year longitudinal follow-up and the large number of subjects who participated.”
The other implication of their work, Yaffe said, is that a blood test for β amyloid may have potential. This idea remains controversial, however. Zetterberg said it is not clear which physical process plasma Aβ levels reflect, since plasma Aβ has not shown a strong correlation with Aβ in the CSF (see Hansson et al., 2008). “It would be great to see how plasma Aβ levels correlate with PIB retention in the brain,” Zetterberg suggested. Yaffe points out that few studies have measured Aβ in both CSF and blood, and more comparisons should be done. This will soon happen, according to Les Shaw at the University of Pennsylvania in Philadelphia, and co-director of the ADNI biomarker core, as ADNI has collected these data and they will be analyzed this year using the INNO-BIA assay. Shaw also emphasized the movement in the AD field toward standardizing study design, including all methods used and performance, which will make comparisons between studies more meaningful.
Researchers agree that it remains to be seen if a blood test for AD will ever be viable. Yaffe noted that their study looked at averaged results for large groups of people. “We don’t know how this translates into an individual’s risk,” she said. Zetterberg speculated that even if the plasma Aβ results are robust and reflect a process happening in the brain, a blood test would probably not be useful as a diagnostic for AD. Instead, such a test would more likely indicate heightened risk, analogous to measuring cholesterol for heart disease.—Madolyn Bowman Rogers.
Yaffe K, Weston A, Graff-Radford NR, Satterfield S, Simonsick EM, Younkin SG, Younkin LH, Kuller L, Ayonayon HN, Ding J, Harris TB. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA. 2011 Jan 19;305(3):261-6. Abstract
Breteler MM. Mapping out biomarkers for Alzheimer disease. JAMA. 2011 Jan 19;305(3):304-5. Abstract