Most of the research on Alzheimer’s biomarkers to date has been done in predominantly white populations, but a few small studies have hinted at possible racial differences. A paper in the January 7 JAMA Neurology supports this idea. Researchers led by John Morris at Washington University in St. Louis found less cerebrospinal fluid tau but more hippocampal atrophy in at-risk African-Americans than in white counterparts. The differences only cropped up in subgroups, however, and the small number of participants render any conclusions tentative. Do the findings represent a true biological difference, or merely reflect recruitment biases and social factors that the study could not account for?
- The largest AD biomarker study of African-Americans to date finds some racial differences.
- African-American ApoE4 carriers had lower CSF tau than white E4 carriers.
- It is unclear if the findings reflect biology, or are due to environmental factors or recruitment bias.
Other researchers said that larger cohorts will be needed to answer this, but called the WashU findings a useful step. “This study represents the largest sample size of African-American individuals with positron emission tomography and CSF data to date,” Lisa Barnes at Rush University Medical Center, Chicago, wrote in an accompanying editorial. Adam Brickman at Columbia University in New York City noted, “This certainly provides more evidence that race, ethnicity, and likely other demographic variables need to be considered explicitly in future work related to Alzheimer’s biomarkers.”
Efforts to study AD biomarkers in diverse populations have been hampered by poor recruitment of minorities. In St. Louis, African-Americans make up about 18 percent of the population, but initially comprised only 3 percent of the observational cohort at the Knight Alzheimer’s Disease Research Center at WashU. Over the last two decades, researchers have increased participation to 18 percent, and last October hosted a conference to discuss strategies for boosting African-American enrollment (Oct 2018 conference news). There, Morris and William Hu from Emory University, Atlanta, reported independent preliminary data suggesting CSF tau runs lower in African-Americans than in whites (Oct 2018 conference news).
Morris and colleagues now publish the cross-sectional data from this observational cohort. Out of 1,255 participants with biomarker data, 173, or 14 percent, were African-American. For specific biomarkers, the numbers were smaller, however, because not all participants consented to all procedures. A total of 143 African-Americans underwent MRI scanning, 87 donated CSF, and 65 had PiB PET scans. All participants had clinical assessments within six months of biomarker measurement. Two-thirds of both African-American and white participants had normal cognition, with the remainder mostly CDR 0.5 or 1.
The researchers saw no differences in amyloid load by race, whether measured by PET or CSF. On MRI, however, they recorded smaller hippocampal volumes in African-Americans with a family history of dementia than in non-Hispanic whites with such history, but no differences among those without a family history. CSF total tau was lower among the African-Americans than the whites, averaging 294 pg/ml versus 443 pg/ml, and p-tau181 likewise ran low, averaging 53 pg/ml in African-Americans versus 71 pg/ml in whites. Total tau and p-tau are considered markers of neurodegeneration and toxic pathological forms of tau, respectively. The tau differences were almost entirely driven by ApoE4 carriers. Noncarriers only trended toward lower t-tau compared with whites. However, the subgroup sizes were small. Only 37 African-American carried the ApoE4 allele.
The tau findings agree with Hu and colleagues, who likewise reported lower CSF t-tau and p-tau in African-Americans (Howell et al., 2017; Oct 2018 conference news). “This is an important replication study because we can now say this phenomenon is not restricted to African-Americans in the Atlanta area,” Hu wrote to Alzforum.
Intriguingly, other studies have found that the ApoE4 allele confers less AD risk on African-Americans than whites, and that seems to jibe with the lower tau levels (Farrer et al., 1997). It hints that ApoE4, which has been shown to worsen tau pathology, exerts less sway over tau in African-Americans (Sep 2017 news). “We are accumulating data that point to African-Americans responding differently to the early brain changes of Alzheimer's disease,” Hu noted.
Other researchers said it is too early to draw conclusions, pointing to limitations in the data set. There were several differences between the African-American and white cohorts, with the former consisting of a higher percentage of women and having fewer years of education, less family history of dementia, a higher average body mass index, and higher blood sugar. While adjusting for all of these factors did not change the findings, WashU researchers did not correct for other possible environmental differences or sources of bias. Jennifer Manly at Columbia University in New York noted that the study did not examine measures of socioeconomic status, access to healthcare, or race-specific stressors. “Thus, the results are subject to residual confounding,” she wrote to Alzforum.
In addition, studies like this often suffer from recruitment bias, where people who volunteer to participate are not typical of the general population. One sign this may be the case here, Manly noted, is that the WashU researchers saw no differences in cerebral ischemic lesions by race. In most population studies, these indicators of cerebrovascular disease are higher in African-Americans than age-matched whites. The limited numbers of people who chose to participate in biomarker substudies may have introduced further recruitment bias, Manly added. Brickman concurs. “It is too soon to determine whether the reported differences are due to true underlying differences, to environmental exposures, to systematic sampling bias, or to some combination of these factors,” he wrote.
Morris agrees these are valid concerns. “We will need larger samples of African-Americans to fully understand whether our findings are confirmed or refuted,” he told Alzforum. “Increasing the diversity of our research cohorts is imperative.”
If the finding of lower CSF tau holds up, it would imply the need for distinct diagnostic cutoffs in African-Americans and whites. In practice, that might be difficult to apply, because many people in the U.S. have mixed genetic heritage, Hu noted. “One solution would be to identify genetic factors that influence CSF tau values,” he suggested.
Barnes advocates for large collaborative efforts to increase minority representation in research studies. “As the field moves toward a biological definition of AD, the under-inclusion of minority populations in AD research will significantly hinder our progress as a field,” she predicted.—Madolyn Bowman Rogers
- Alzheimer’s Researchers Seek Advice on How to Include African-Americans
- Do African-Americans Have More, or Different, Alzheimer’s Disease? Too Little Data to Tell
- ApoE4 Makes All Things Tau Worse, From Beginning to End
- Howell JC, Watts KD, Parker MW, Wu J, Kollhoff A, Wingo TS, Dorbin CD, Qiu D, Hu WT. Race modifies the relationship between cognition and Alzheimer's disease cerebrospinal fluid biomarkers. Alzheimers Res Ther. 2017 Nov 2;9(1):88. PubMed.
- Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56. PubMed.
- Morris JC, Schindler SE, McCue LM, Moulder KL, Benzinger TL, Cruchaga C, Fagan AM, Grant E, Gordon BA, Holtzman DM, Xiong C. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurol. 2019 Jan 7; PubMed.