CME Author: Vicki Brower
Study Authors: John C. Morris, Suzanne E. Schindler, et al.; Lisa A. Barnes
Target Audience and Goal Statement:
Neurologists, gerontologists, internists, family medicine specialists
The goal was to understand whether racial disparities exist among molecular biomarkers for Alzheimer dementia (AD).
- Are there racial differences in molecular biomarkers for AD?
- If there are, how do they differ?
- What are the implications of these differences for African-Americans?
Study Synopsis and Perspective:
In a cohort study of 1,255 older Americans in one Midwestern city, researchers found significant differences in levels of tau protein and its phosphorylated isoform in cerebrospinal fluid (CSF) between African-American and non-Hispanic white individuals.
Specifically, mean CSF concentrations of total tau were lower in African-American participants than in white participants (293.65 vs 443.28 pg/mL, P<0.001), as were mean concentrations of phosphorylated tau (53.18 vs 70.73 pg/mL, P<0.001), reported John Morris, MD, of the Washington University School of Medicine in St. Louis, and colleagues.
Of note, only participants with an APOE ε4 allele showed these differences, which suggests “a significant race-by-APOE ε4 interaction,” the authors wrote in JAMA Neurology. There was no difference between African-American and white participants for CSF concentrations of the 42-residue form of amyloid beta protein.
“Few studies have compared molecular biomarkers of AD in African-American individuals and white individuals to determine whether or not there are potential disparities in underlying AD mechanisms. There also could be important practical considerations should there be racial difference in AD biomarkers,” the authors wrote.
Morris and colleagues used biomarker data from 1,255 adults enrolled in longitudinal studies at the Knight Alzheimer Disease Research Center at Washington University who had at least one Alzheimer’s biomarker study from 2004 to 2015. Participants averaged about age 71, and 173 people (13.8%) were African-American. Two-thirds had normal cognition; the remaining one-third were in the earliest stages of Alzheimer’s disease.
Besides reduced CSF levels of total tau and phosphorylated tau, African-American participants with a reported family history of dementia had lower hippocampal volumes than white individuals (6,418.26 vs 6,990.50 mm3, P<0.001). The APOE ε4 allele was associated with increased amyloid PET imaging standardized uptake value ratio in both African-American and white individuals.
Previous data about APOE ε4 and Alzheimer’s in African-American individuals have been mixed, with most — but not all — studies showing a weaker effect of APOE ε4 in the African-American population, despite the allele being much more frequent, said Lisa Barnes, PhD, of Rush University Medical Center in Chicago, in an accompanying editorial.
“The APOE ε4 allele has been found to be the most robust driver of AD pathologic characteristics in white individuals,” she wrote. “Given the weaker association of APOE ε4 with risk of Alzheimer’s disease in African-American individuals, however, one would have expected the association with pathologic characteristics to be weaker as well, consistent with what the study by Morris and colleagues reported,” she commented.
In an earlier study Barnes co-authored, APOE ε4 in African-American individuals was related to a faster rate of decline in episodic memory compared to white individuals, but not in other cognitive domains, suggesting that the weakened effect of this allele may stem from brief global measures that may obscure its specific effect on episodic memory, she added.
Sample sizes varied significantly across different biomarker categories: African-American individuals were as likely as white individuals to have MRI data but less likely to have CSF data, and PET imaging was low for both groups, Barnes observed.
This study also is limited by its cross-sectional nature: biomarkers could not be tied to Alzheimer’s progression, Morris and colleagues noted. People participating in Alzheimer’s biomarker studies are not representative of the overall population and results may not be applicable to others. Findings should be interpreted with caution until they can be confirmed or refuted with larger studies, they added. Another limitation of the study is that the assessment of socioeconomic status was restricted to education level, and that assessment of cerebrovascular disease was limited to ischemic lesions on brain MRI findings.
“It is not clear how differential participation across biomarkers may have influenced the reported results, as persons agreeing to undergo the various procedures were likely not random,” Barnes wrote. And other factors including comorbid diseases, and negative cultural experiences that may contribute to racial differences in Alzheimer’s and cognitive impairment might have influenced results but were not included as covariates, Barnes added.
JAMA Neurology, online Jan. 7, 2019; DOI:10.1001/jamaneurol.2018.4249
Editorial: JAMA Neurology, online Jan. 7, 2019; DOI:10.1001/jamaneurol.2018.3444
Study Highlights: Explanation of Findings
This study, the authors noted, is likely the first to examine racial differences in molecular biomarkers of AD in which the cohort contributed data both on amyloid concentrations as visualized on PET scans and on concentrations of tau in CSF.
The authors concluded that with their results, normal versus abnormal values of CSF levels of both types of tau as a marker of neurodegeneration “must be race adjusted when African-Americans individuals are considered for the framework’s amyloid/tau/neurodegeneration (A/T/N) classification scheme for AD.”
Regarding their findings of lower levels of tau and phosphorylated tau in African-Americans in the study, they note that they “are not readily explained by the presence of comorbid cerebrovascular disease. Given recent evidence that APOE ε4 influences tau pathogenesis and tau-mediated neurodegeneration independent of Aβ pathologic characteristics, “it is possible that the interactions of APOE ε4 with tau in African-American individuals differs from its interactions with tau in white individuals, perhaps similar to the observed weaker association in African-American individuals of APOE ε4 with AD,” the authors hypothesized.
Ultimately, “racial differences in Alzheimer’s biomarkers suggest possible race-dependent biological mechanisms that contribute to expression of disease,” authors wrote.
Morris observed that there are at least three major implications of these findings:
“First, in almost all studies of molecular biomarkers of Alzheimer’s disease, the findings from amyloid PET imaging and assays of cerebrospinal fluid concentrations of Alzheimer’s proteins have been analyzed without regard to the racial or ethnic origins of individual research participants — that is, the findings have simply been pooled, with the assumption that everyone is the same,” he told MedPage Today. But “at least for tau biomarkers, race-specific analyses and cut-offs are needed.”
Second, differences in CSF total tau and phosphorylated tau levels may indicate differences in biological mechanisms underlying Alzheimer’s disease between African-American and white individuals that contribute to the expression of the disease.
Third, the results “underscore the fact that, as a research community, we need to do a much better job of being welcoming to people of color,” Morris said. “Almost everything we’ve learned about Alzheimer’s disease in the past 35 years has come from studies in research participants who were almost totally white.”
“As the U.S. population is becoming increasingly diverse, our research populations need to reflect that diversity,” Morris stated. “Otherwise, what we learn about the disease and how to effectively treat it may apply only to white people.”
Barnes agreed, noting that the underrepresentation of African-Americans and other minorities in studies will hinder progress in developing a biological definition of AD, “and the race to end AD will not be shared with our most vulnerable, at-risk populations.” Numbers of subjects needed to definitively understand association of biomarkers to race are currently lacking, she noted.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco