Some Misleading Plasma Biomarkers of Alzheimer’s Disease in Black Populations – A Conversation with Susan E. Schindler, MD, PhD

According to the results of a study published in Neurology.

The data for this study was collected at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center. Community-dwelling older adults with or without cognitive impairment underwent cognitive assessment, provided a blood sample, and underwent cerebrospinal fluid (CSF) sampling and/or amyloid positron emission tomography (PET) .

Individuals with CSF biomarker data and sufficient plasma aliquots available were matched 1:1 between the cohorts of self-identified African American (AA; n=76) and non-Hispanic white (NHW; n = 76). Cohorts were assessed for plasma biomarkers of amyloid (and Aβ42/Aβ40 ratio), tau (p-tau181 and p-tau231) and neuroaxonal damage (neurofilament light chain [NfL]) using immunoprecipitation-high performance mass spectrometry or Simoa immunoassays. Plasma biomarker results were compared to CSF ​​or PET biomarker results.

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The AA and NHW cohorts had a median age of 68.4 years (interquartile range [IQR]64.9-73.2) and 68.4 (IQR, 64.1-73.1) years, 58% and 51% were female, and 42% and 42% were apolipoprotein E carriers (APOE) e4, respectively.

According to amyloid PET scan (median centiloids, 2.3 vs 10.1; adjusted P =.02) and CSF biomarkers (22% versus 43%; P = 0.003), the AA cohort had lower mean levels of cerebral amyloidosis.

In the plasma biomarker analysis, the AA cohort had a significantly higher concentration of Aβ42 (median, 41.9 vs. 40.9 pg/ml; adjusted P = 0.03) and a higher Aβ42/Aβ40 ratio (median, 0.1047 vs. 0.0963; adjusted P <.0001 the aa and nhw cohorts did not differ for plasma concentrations of a vs pg p-tau181 p-tau231 .2 or nfl respectively.>

Compared to CSF ​​biomarkers, plasma biomarker results were consistent for Aβ40 and the Aβ42/Aβ40 ratio. Other biomarker results differed in CSF assessment, in which the AA cohort was associated with similar Aβ42 (median, 735 vs 682 pg/ml) and decreased p-tau181 (median, 31 vs 38.0 pg/ml;adjusted P =.0008) and NfL (median, 644 vs. 736 pg/mL; adjusted P =0.08) compared to the NHW cohort.

Among plasma biomarkers, the Aβ42/Aβ40 ratio was most strongly correlated with CSF Aβ42/Aβ40 (r, 0.52) and PET centiloids (r, -0.30). Similarly, plasma Aβ42/Aβ40 exhibited the highest area under the receptor operating characteristic curve (ROC AUC) in predicting CSF amyloid status (ROC AUC 0.86 vs 0.64-0.76) and PET (ROC AUC 0.86 vs 0.55-0.74).

In a model that accounted for covariates, the plasma Aβ42/Aβ40 model (ROC AUC, 0.90) outperformed the model with only covariates (ROC AUC, 0.82) in predicting CSF Aβ42/Aβ40. In this combined covariate-plasma Aβ42/Aβ40 model, individuals who had cognitive impairment (odds ratio [OR], 9.2; 95% CI, 1.9-46; P =.007), were APOE carriers e4 (odds ratio [OR], 5.7; 95% CI, 2.3-14; P = 0.0002), or were older (OR, 1.2; 95% CI, 1.03-1.21; P = 0.007) and were more likely to have CSF Aβ42/Aβ40 positivity.

In a covariate-only model, AA individuals were associated with a reduced risk of CSF Aβ42/Aβ40 positivity (OR, 0.27; 95% CI, 0.12-0.64; P =.003). Similarly, AA individuals had a reduced risk of positivity in p-tau181, p-tau231, and NfL plasma-based models (all P ≤.007). Similar results were observed to predict amyloid PET positivity.

This study may have been limited by the small number of individuals (n = 7) in each cohort who had cognitive impairment.

These data indicated that plasma Aβ42/Aβ40, upon which the C2N Diagnostics PrecivityAD plasma Aβ42/Aβ40 assay is based, more accurately predicted CSF or PET amyloid status in AA and NHW individuals compared to other plasma biomarkers. Taken together, these results suggest that prediction of AD risk using other plasma biomarkers would not be consistent across a diverse patient population.

We spoke with Suzanne E. Schindler, MD, PhD, associate professor of neurology, Washington University School of Medicine in St. Louis, Missouri, and lead author of the study.

What was the motivation for your study?

Doctor Schindler: We are trying to develop blood tests for Alzheimer’s disease. There are other tests for Alzheimer’s disease, such as amyloid positron emission tomography (PET) and cerebrospinal fluid tests. But the scans are very expensive and few centers do them systematically. More centers can perform cerebrospinal fluid tests, but many patients are not enthusiastic about having a lumbar puncture. Basically, the other tests are just not practical.

Unfortunately, most tests for Alzheimer’s disease have only been validated in non-Hispanic white cohorts. There has been evidence in recent years that cerebrospinal fluid testing has a different meaning in African Americans and non-Hispanic whites. As many researchers are developing blood tests for Alzheimer’s disease, we wanted to evaluate the performance of these blood tests in different groups, asking whether they give consistent results whether the patient is African American or white.

What did your study find?

Doctor Schindler: A blood test, for Aβ42/Aβ40, gave consistent results between African American and non-Hispanic white patients. For 3 other blood tests, the results were inconsistent, and relying on these results could lead to a disproportionate misdiagnosis of African Americans.

What do these results mean for clinical practice?

Doctor Schindler: The only blood test for Alzheimer’s disease that is currently available for clinical use is the test that worked well, so that’s good news. But these other tests are in preparation. I think our results demonstrate that companies developing these tests need to evaluate them in diverse cohorts.

One of the potential reasons why the Aβ42/Aβ40 assay performed better is that it is a ratio of 2 proteins. Using ratios instead of a single protein concentration could help account for variation between people.

Racial norms are a big topic in medicine right now and there are concerns that using different thresholds for different races has actually exacerbated health care disparities. I think a better solution is to either use a test that works consistently across groups, or to consider underlying differences between groups instead of adjusting for race.

What do you think these findings mean for genetics or the cause of AD in general?

Doctor Schindler: A somewhat confusing aspect of our findings, and other work, is that it appears that levels of amyloid in the brain are lower in African Americans, even when you adjust for age and gender. . A recent study published in JAMA found that rates of dementia in Hispanics and blacks are higher than in whites, so they might be expected to have more amyloid, not less. We are still trying to understand the reason for these differences.

Do you think the results of this study are generalizable to other areas of neurology or medicine in general, or should the diagnostic tools be critically evaluated to see if they are generalizable to all populations ?

Doctor Schindler: Almost all research studies are based on largely non-Hispanic white populations. We have very low representation of minority groups, especially black people, in research studies. This is a big problem that prevents generalizing research findings to the general population.

I think when you’re diagnosing someone with a disease that has far-reaching implications for their health, you want to make sure you’re getting accurate results, regardless of the person’s race or ethnicity. The United States Food and Drug Administration publishes guidelines stating that you must have a diversity plan for clinical trials. They haven’t released any tips for diagnostics yet, but I can certainly imagine that happening.

Disclosure: Several authors have declared industry affiliations. Please refer to the original article for a full list of disclosures.


Schindler SE, Karikari TK, Ashton NJ, et al. Effect of race on the prediction of cerebral amyloidosis by plasma Aβ42/Aβ40, phosphorylated tau and neurofilament light. Neurology. 2022;10.1212/WNL.0000000000200358. doi:10.1212/WNL.0000000000200358

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