Conference Coverage

Alzheimer’s disease plasma biomarkers may be nuanced



Plasma biomarkers such as amyloid-beta 40 and 42, phosphorylated tau 181 and 217, and neurofilament light hold great promise for diagnosing and determining a prognosis for Alzheimer’s disease. Such tests are likely to be widely available in the near future.

Michelle Mielke, PhD, is a professor of epidemiology and neurology at the Mayo Clinic in Rochester, Minnesota.

Dr. Michelle Mielke

But work remains to be done to translate findings from academic studies to the more general population. A key consideration is that plasma levels of these biomarkers could be affected by other conditions, which could in turn skew test results, according to Michelle Mielke, PhD, who spoke on the topic at the 2021 Alzheimer’s Association International Conference.

“The markers, which we’ve published on as well, look really promising. But they have primarily been looked at in more specialty clinics or memory clinics, and have not been examined in the general community. The goal of this presentation was really just to take a look at this in the community, in older individuals that have multiple comorbidities, and to understand what factors might affect the levels of these markers. Because as we do go forward and develop cut points, we are going to have to consider these aspects,” said Dr. Mielke in an interview. She is a professor of epidemiology and neurology at the Mayo Clinic in Rochester, Minn.

Case in point

To illustrate the point, Dr. Mielke presented data from her group, which analyzed P-tau 181 and P-tau 217 data from 1,329 Mayo clinic patients. Of that total, 1,161 were cognitively unimpaired (CU), 153 had mild cognitive impairment (MCI), and 15 had dementia. The median age was 67, 55% were male, and 26% had the APOE e4 allele.

After adjustment for age and sex, there were statistically significantly elevated levels of both biomarkers among patients who had tested positive for amyloid and patients who had had a stroke or myocardial infarction, and in the presence of chronic kidney disease (CKD). There also was a trend towards an increase of biomarker levels with increasing body mass index. The differences remained even after the analysis was restricted to individuals who were amyloid negative.

The researchers then looked more closely at the impact of CKD, stroke, and MI on P-tau cut points and the ability to predict abnormal amyloid positron emission tomography (PET) scans. They defined an abnormal range as 1.96 standard deviation units beyond the mean among amyloid-negative individuals who are cognitively impaired. They excluded subjects with those risk factors and then established new cut points in the absence of the factors. The approach led to a significant change for the cutoff of P-tau 181 values, from 1.57 pg/mL or greater for individuals without stroke, MI, or CKD, and 1.75 pg/mL or greater for individuals with one such factor. There was little difference in the cutoff value for P-tau 217, from 0.25 pg/mL to 0.26 pg/mL.

Among people without a history of stroke, MI, or CKD, a P-tau 181 cutoff of 1.57 pg/mL or greater had an area under the receiving operating characteristic (AUROC) value of 0.717 (95% confidence interval, 0.691-0.744), compared with an AUROC of 0.687 (95% CI, 0.662-0.712) at a cutoff of 1.75 pg/mL or greater among people with those conditions. For P-tau 217, the values were 0.737 pg/mL (95% CI, 0.712-0.762) and 0.724 pg/mL (95% CI, 0.699-0.748), respectively.

“The sensitivity was better when they excluded those individuals with these conditions. Specificity was slightly, but not significantly, lower,” said Dr. Mielke during her talk.


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