In life, where people end up often tells less than how they got there. Could the same be true for biomarkers? While cross-sectional studies have established that cerebrospinal fluid levels of tau and Aβ42 are abnormal years before a diagnosis of Alzheimer’s disease, longitudinal data on CSF changes in cognitively normal people has been lacking. Now, researchers led by Marilyn Albert at Johns Hopkins University, Baltimore, Maryland, report that not only does tau rise and Aβ42 fall as people develop the disease, but the rate of change in the ratio of these markers predicts the onset of impairment better than do baseline values. The data, published in the October 16 Neurology, suggest that the dynamics of the tau/Aβ42 ratio might be particularly useful for tracking disease progression in clinical trials, Albert said.
“This type of study gives us a better understanding of the disease process from a molecular perspective. The fact that the changing tau/Aβ42 ratio captures disease progression better than either biomarker alone speaks for both processes going on in parallel in this age group,” said Henrik Zetterberg at the University of Gothenburg, Sweden. He was not involved in the work. Current models of disease progression hold that Aβ changes first, followed by tau a few years before symptoms appear (see ARF webinar; ARF related news story; ARF news story). To test this theory, Zetterberg suggested that future studies should follow even younger cohorts to see if tau is in fact stable in this group.
Several previous cross-sectional studies established that low Aβ42 and high total tau and phosphorylated tau (p-tau) in CSF in older adults increased the odds of developing cognitive impairment over the next several years (see ARF related news story on Fagan et al., 2007; Li et al., 2007; Gustafson et al., 2007). Likewise, cross-sectional studies in familial AD populations found abnormal CSF Aβ42 decades before the expected age of onset, and abnormal tau a few years before (see ARF related news story; ARF news story). In longitudinal studies of people with AD, however, biomarkers show little change over time, suggesting values have plateaued.
Albert and colleagues wanted to get a closer look at how CSF biomarkers change over time much earlier in the disease, well before symptoms emerge. First author Abhay Moghekar followed 265 cognitively normal participants with an average age of 57 for about eight years, at the end of which 53 had developed mild cognitive impairment or dementia. In these participants, the first symptoms of forgetfulness appeared about five and a half years after the study began. The cohort was predominantly Caucasian, highly educated, and had a family history of dementia.
As expected from previous studies, people who had low Aβ42 or high p-tau, tau/Aβ42, or p-tau/Aβ42 at baseline had 50 percent higher odds of progressing to impairment compared with those with normal biomarkers. Changes over time provided a more powerful indicator, however. People whose tau/Aβ42 or p-tau/Aβ42 ratios climbed fastest had almost double the chance of developing cognitive symptoms, compared with those with relatively stable ratios, the authors report. In ongoing work, Albert is looking at how these CSF biomarkers relate to changes in imaging and cognitive tests over time. The goal is to find a combination of biomarkers that could diagnose an individual’s chances of developing AD, Albert said. At the moment, CSF biomarkers are predictive only at the group level.—Madolyn Bowman Rogers
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