26 Oct 2018

• Alzheimer’s disease is twice as common among African-Americans than non-Hispanic whites. Or is it?
• African-Americans have greater cerebrovascular risk factors. Do those lead to AD, or to vascular or mixed dementia?
• African-Americans have differences in their CSF and ApoE. What do they mean?
• African-Americans live with adverse social determinants of health. Do they lead to Alzheimer’s as currently defined?

This is but a sampling of the scientific questions that researchers, patient advocates, and other stakeholders grappled with on October 10 at Washington University in St Louis. They met for a federally funded workshop called African-American Participation in AD Research: Effective Strategies. The sparse nature of the data available thus far to answer these and other questions highlighted that scientists across the country would be well-advised to emulate and expand local efforts that have been effective in engaging this important minority population (see Part 1 of this series).

According to a Brookings Institution analysis of projections by the U.S. Census Bureau, black people over 65 currently make up 9 percent of the U.S. population, and their share will grow to 13 percent by 2060 (Frey et al., 2012). These demographics mask higher population fractions in parts of large cities such as New York or Chicago, and mid-size cities such as St. Louis, Detroit, and many other urban areas. And yet black people consistently make up a far lower proportion of participants in observational studies and clinical trials, meaning even basic questions remain unanswered for this population.

For starters, whether Alzheimer’s is more common in African-Americans remains unclear. Some population-based or memory clinic cohorts report a black AD incidence twice that of whites (e.g. Tang et al., 2001; Weuve et al., 2018). But other recent data suggest racial differences may not be as large as previously thought. Rachel Whitmer of the University of California, Davis, School of Medicine, studies electronic health records of patients in the Kaiser Permanente health care system. This approach allows her to tap new populations unlikely to participate in research, such as rural people or people with diabetes-related low-blood-sugar episodes who are too sick to join studies. Analyzing dementia incidence between the years 2000 to 2013 among 274,283 members of Kaiser Permanente, Whitmer was surprised to discover that while Asian Americans, at 15 percent, had the lowest rate of all racial groups, the difference between blacks (26 percent) and whites (19.3 percent) was smaller than she had expected (Mayeda et al., 2016). 

The issue remains obscure because some studies use all-cause dementia or a clinical diagnosis as an outcome, while others use an etiological definition of Alzheimer’s disease marked by its signature postmortem neuropathology or biomarkers. Equating different forms of dementia makes it difficult to isolate cerebrovascular from amyloid- and tau-related pathways, cautioned David Knopman from the Mayo Clinic, Rochester, Minnesota. The use in dementia diagnosis of cognitive testing against population norms may further skew prevalence numbers on African-Americans, some of whom underperform on those tests as a result of growing up with educational disparities (Barnes and Bennett, 2014). 

One attempt at understanding environmental influences on dementia came from Sujuan Gao, a biostatistician at Indiana University School of Medicine, Indianapolis. Gao summarized incidence results from a longstanding study comparing brain aging in some 4,100 African-Americans from around Indianapolis to 4,400 Yoruba people in the city of Ibadan, Nigeria. The study enrolled a first wave of volunteers in 1992 and a second in 2001, and has conducted up to seven follow-up observations with them by now. Led in the U.S. by Hugh Hendrie, also at University of Indiana, this observational cohort put the incidence of Alzheimer’s disease among African-Americans in Indiana at more than twice that of the Nigerian volunteers. In addition, their measures of hypertension, diabetes, stroke, smoking, cholesterol, and body-mass index were higher than those of the Yoruba.

Intriguingly, the later-born cohort enrolled in 2001 had a steep reduction in AD incidence relative to the first cohort among African-Americans, but stayed constant in the Yoruba. What had changed, Gao asked? For the second Indiana cohort, years of education and white-collar jobs had gone up, while rural upbringing and smoking had gone down. The participants’ hypertension and diabetes rates had risen, but they received medical treatment for those risk factors.

Analyzing each factor individually, Gao showed that blood-pressure-lowering medication in particular brought down risk of AD. Statin treatment did, too, though it was unclear if the protection worked through lowering blood cholesterol levels, as those remained high.

Diabetes was more frequent and more severe among the American than Nigerian study participants. When the researchers added participants’ electronic health records to the study’s own data, they discovered that people who were developing dementia had a notable decline in their previously elevated blood glucose levels during the five years before they became symptomatic. A subsequent comparison with white people in the U.S. showed that this pre-dementia blood glucose decline appeared to be particular to African-Americans (Hendrie et al., 2017; Hendrie et al., 2018). In an ongoing WashU biomarker study (see below), the plasma glucose marker hemoglobin A1c was elevated at baseline in cognitively normal African-Americans relative to otherwise matched non-Hispanic whites, but no follow-up data are available yet to assess change over time.

Taken together, Gao believes that the declining rates of dementia among African-Americans in the Indiana-Ibadan cohort reflect both improved life course determinants and better medical management of cerebrovascular risk factors, especially hypertension.

Whitmer noted that previous studies have underestimated the effect of high blood pressure on cognitive aging in African-Americans, because a shorter life expectancy exacerbates their underrepresentation in epidemiological aging studies (Mayeda et al., 2016). A selective survival bias occurs because health disparities accelerate aging in African-Americans, said Jennifer Manly of Columbia University, New York. This shortens life span in some, for example due to complications of hypertension; which, in turn, distorts racial comparisons of cognitive function in old age (Zahodne et al., 2016; Barnes and Bennett, 2014). Manly considers longer education to be the factor that may have had the greatest impact in the later-born Indiana-Ibadan cohort. Her analyses of the longstanding observational Washington Heights-Inwood Community Aging Project (WHICAP) cohort in north Manhattan also showed less memory decline in later-born people who received more education.

At the workshop, Lisa Barnes of Rush University, Chicago, briefly previewed emerging results from her ongoing cohort studies of brain aging in African-Americans in the Chicago metropolitan area (see Part 1). Her data tend to support the importance of both cerebrovascular health and cognitive reserve due to life course factors. Barnes’ team sees that black participants appear to be particularly vulnerable to microinfarcts, i.e., microvascular lesions in the brain that are visible on MRI. Compared with white participants in comparable studies at Rush, dementia in African-Americans rose more steeply with the number of microinfarcts they had.

What about neuropathology? Brain donation rates are increasing in the Rush study, though the 70 autopsies conducted to date still offer only a small data set. Thus far, Barnes said, pathology comparisons between racial groups indicate that black study volunteers without dementia at baseline are not much different from whites. Among people who had dementia, however, more blacks than whites had mixed pathology consisting of amyloid plaques, neurofibrillary tangles, infarcts, Lewy bodies, and arteriolar sclerosis; fewer blacks than whites had “pure” AD, i.e., only plaques and tangles (Barnes et al., 2015). 

Genetically, too, no large differences between African-Americans and Caucasian people have emerged. The genetic architecture of aging-related cognitive decline is similar overall. Advanced sequencing techniques are yielding some variants, for example in the ABCA7 gene. But none have jumped out for a large effect size or high frequency. Neither have any picked up momentum by repeated confirmation in independent sample sets, or caught researchers’ imaginations for suggesting a tangible biological mechanism that might be unique to African-Americans (e.g. Raj et al., 2017; Mez et al., 2017; Cukier et al., 2016; Kunkle et al., 2017). 

Goldie Byrd of Wake Forest University, Winston-Salem, North Carolina, a co-author on many of these papers, told Alzforum that she suspects differences in ADRD between black and white Americans have less to do with genetics and more with the long-term health consequences of living with racism. Some researchers at the workshop called for more research on neuronal, vascular, and immunological mechanisms of chronic stress.

What about biomarkers? Little is known about differences in African-Americans specifically because available data sets are so small, said John Morris of Washington University St. Louis, who hosted the workshop. However, researchers presented unpublished findings that spurred much interest.

One study is being led by William Hu of Emory University, Atlanta. Hu recalled that his interest in biologic differences was sparked during his neurology residency at the University of Pennsylvania in Philadelphia, where researchers incorporate CSF tests into their diagnostic workups for people with clinical signs of Alzheimer’s disease. “Often, African-Americans did not have the CSF results that would make me comfortable telling them they had AD. This made me curious,” Hu said. Did they have something else that presented clinically as AD? Was it vascular dementia mixed with AD? Or was there something truly different in how their AD developed?

Once at Emory, Hu started a biomarker study with the university’s research registry for African-Americans. It currently follows 135 older black people whose cognition ranges from normal to mild dementia. Hu has two papers under review or in preparation; at the workshop he only hinted at the overall finding. While some CSF analytes are the same among black and white participants—Aβ42, NfL, sICAM-1, sAPPα, and sAPPβ—other markers differ. These include total tau, phospho-tau 181, the neuroinflammation marker vascular cell adhesion molecule 1 (sVCAM-1, July 2018 conference news), the endopeptidase neprilysin, and others.

A previous data freeze on 65 registry participants is published. It indicated that while otherwise matched black and white volunteers had comparable levels of CSF Aβ42 and Aβ42/Aβ40 ratio, black participants had lower levels of CSF tau and more white-matter hyperintensities. That paper suggested that cerebrovascular factors tend to play a larger role in cognitive impairment in African-Americans than in Caucasians (Howell et al, 2017). The new data support this trend. “We now have many analytes that are different between older healthy African-Americans and whites,” Hu said in St. Louis.

Converging evidence from WashU is currently in press. In St. Louis, WashU’s Morris showed a cross-sectional analysis of 903 participants 45 and older, including 87 African-Americans, all of whom were comprehensively assessed from 2004 to 2015 with at least one MRI, amyloid PET, and CSF assays for Aβ42 and tau. This presentation did not include neurovascular CSF analytes such as sVCAM-1; even so, the canonical AD CSF signature confirmed and expanded Hu’s finding of same Aβ42 but lower tau.

The St. Louis area cohort, too, showed no difference in amyloid burden by race. In both black and white people, deposition increased with age. It was higher in ApoE4 carriers and as people approached the onset of dementia. The hippocampus was smaller in symptomatic people of both races. That said, CSF tau was different. Both total tau and phospho-tau were significantly lower in African-Americans than whites. Both analytes rose in the expected overall pattern, in that when a person was symptomatic his or her CSF tau was elevated. But the numeric tau values were always lower in African-Americans than in otherwise matched non-Hispanic whites.

Curiously, ApoE appeared to have the opposite effect on CSF tau in African-Americans than in whites. Among white people, as expected, CSF t-tau and p-tau are higher in those who carry the APOE4 AD risk allele than those who do not. Among African-Americans the opposite is true, whereby CSF t-tau and p-tau measurements came in lower when a person carried APOE4. This difference is intriguing because studies by other groups have reported that APOE4 does not boost AD risk equally across race. Even though ApoE4 is more frequent in African-Americans, it does not appear to drive up their AD risk much (e.g., Evans et al., 2003; Weuve et al., 2018). 

At the workshop, scientists debated in the auditorium and hallways what Hu and Morris’s data might mean. Potential interactions between ApoE, tau, cholesterol, and neuroinflammatory pathways in microglia have become an active area of study (e.g. July 2018 conference news; Kang et al., 2018). Might there be a factor in African-Americans that protects against the downstream effect of amyloid deposition, or of ApoE, on tau? If so, this could point to a yet-unknown molecular mechanism that could yield therapeutic targets for Alzheimer’s disease. Alas, the Emory and WashU CSF data sets, while the largest available at this point, are still far too small to draw conclusions, Morris and Hu agreed. “We need a national cohort,” Hu said. The two centers are now collaborating.

A larger data set would also allow researchers to better understand layers of diversity among people of color in the U.S. more broadly. For example, recent black immigrants from Caribbean countries have quite different early life experiences than African-Americans whose families have been in the U.S. for generations, said Jonathan Jackson of Massachusetts General Hospital, Boston. Life experience could influence CSF measures; as could socioeconomic circumstances. Hu noted that participants from around the more affluent Emory University Medical School area may differ from those around Atlanta’s Grady Memorial Hospital, which serves an urban population with greater health disparities. The African-American participants in the WashU cohort had on average 13 years of education, which exceeds their average across the country, said Manly.

For her part, Manly considers adverse life course factors going back to childhood to be root causes for racial disparities in health and cognition as people age. On home visits to WHICAP participants, Manly learned that well over half of them were born in southern states in the U.S. She subsequently documented large education disparities. Black people born in the South had fewer years of school, fewer school days per year, and poorer-quality schools than white people born in the South, or than people born in northern states.

Childhood disadvantage carries forward into poor health in multiple ways. For example, Whitmer cited her group’s analysis of 7,423 members of Kaiser Permanente Northern California, including 1,354 black people. It found that being born in a southern U.S. state, in addition to being linked to stroke, also came with a higher risk of dementia, particularly among African-Americans, even though they had since moved to California. A subsequent analysis linking birth in a high infant mortality area to dementia risk reinforced the larger point that place of birth has enduring consequences on dementia risk (Gilsanz et al., 2017; Gilsanz et al., 2018). 

While this workshop focused on African-Americans, understanding diversity in ADRD research is a broader challenge. For one thing, Latinos have even higher rates of dementia than black Americans (e.g., Mayeda et al., 2016). For another, diversity across urban and rural populations, socioeconomic status and cognitive reserve, is difficult to capture. “We want to have breadth, i.e., large populations that are diverse racially, educationally, and geographically. But we also want depth, i.e., brain images, plasma, and CSF. Doing both is hard,” Whitmer said.

In AD therapeutic trials, where efficacy signals have been hard to discern, trialists generally want more tightly defined patient groups selected with biomarkers and phenotypic data that allow them to stratify trial results. They caution that more diversity, if it is poorly understood, may increase noise in the trial data. To understand diversity in Alzheimer’s disease, scientists at the WashU workshop called for larger longitudinal cohorts that track both AD and cerebrovascular biomarkers in diverse populations starting in mid-life, and for adding biomarker outcomes to existing aging cohorts.—Gabrielle Strobel

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References

News Citations

1. Alzheimer’s Researchers Seek Advice on How to Include African-Americans 26 Oct 2018
2. VCAM1: Gateway to the Aging Brain? 17 Jul 2018
3. ApoE Has Hand in Alzheimer’s Beyond Aβ, Beyond the Brain 14 Jul 2018

Paper Citations

1. Tang MX, Cross P, Andrews H, Jacobs DM, Small S, Bell K, Merchant C, Lantigua R, Costa R, Stern Y, Mayeux R. Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology. 2001 Jan 9;56(1):49-56. PubMed.
2. Weuve J, Barnes LL, Mendes de Leon CF, Rajan KB, Beck T, Aggarwal NT, Hebert LE, Bennett DA, Wilson RS, Evans DA. Cognitive Aging in Black and White Americans: Cognition, Cognitive Decline, and Incidence of Alzheimer Disease Dementia. Epidemiology. 2018 Jan;29(1):151-159. PubMed.
3. Mayeda ER, Glymour MM, Quesenberry CP, Whitmer RA. Inequalities in dementia incidence between six racial and ethnic groups over 14 years. Alzheimers Dement. 2016 Mar;12(3):216-24. Epub 2016 Feb 11 PubMed.
4. Barnes LL, Bennett DA. Alzheimer's disease in African Americans: risk factors and challenges for the future. Health Aff (Millwood). 2014 Apr;33(4):580-6. PubMed.
5. Hendrie HC, Zheng M, Li W, Lane K, Ambuehl R, Purnell C, Unverzagt FW, Torke A, Balasubramanyam A, Callahan CM, Gao S. Glucose level decline precedes dementia in elderly African Americans with diabetes. Alzheimers Dement. 2017 Feb;13(2):111-118. Epub 2016 Oct 25 PubMed.
6. Hendrie HC, Zheng M, Lane KA, Ambuehl R, Purnell C, Li S, Unverzagt FW, Murray MD, Balasubramanyam A, Callahan CM, Gao S. Changes of glucose levels precede dementia in African-Americans with diabetes but not in Caucasians. Alzheimers Dement. 2018 Apr 17; PubMed.
7. Mayeda ER, Tchetgen Tchetgen EJ, Power MC, Weuve J, Jacqmin-Gadda H, Marden JR, Vittinghoff E, Keiding N, Glymour MM. A Simulation Platform for Quantifying Survival Bias: An Application to Research on Determinants of Cognitive Decline. Am J Epidemiol. 2016 Sep 1;184(5):378-87. Epub 2016 Aug 30 PubMed.
8. Zahodne LB, Manly JJ, Azar M, Brickman AM, Glymour MM. Racial Disparities in Cognitive Performance in Mid- and Late Adulthood: Analyses of Two Cohort Studies. J Am Geriatr Soc. 2016 May;64(5):959-64. PubMed.
9. Barnes LL, Leurgans S, Aggarwal NT, Shah RC, Arvanitakis Z, James BD, Buchman AS, Bennett DA, Schneider JA. Mixed pathology is more likely in black than white decedents with Alzheimer dementia. Neurology. 2015 Aug 11;85(6):528-34. Epub 2015 Jul 15 PubMed.
10. Raj T, Chibnik LB, McCabe C, Wong A, Replogle JM, Yu L, Gao S, Unverzagt FW, Stranger B, Murrell J, Barnes L, Hendrie HC, Foroud T, Krichevsky A, Bennett DA, Hall KS, Evans DA, De Jager PL. Genetic architecture of age-related cognitive decline in African Americans. Neurol Genet. 2017 Feb;3(1):e125. Epub 2016 Dec 21 PubMed.
11. Mez J, Chung J, Jun G, Kriegel J, Bourlas AP, Sherva R, Logue MW, Barnes LL, Bennett DA, Buxbaum JD, Byrd GS, Crane PK, Ertekin-Taner N, Evans D, Fallin MD, Foroud T, Goate A, Graff-Radford NR, Hall KS, Kamboh MI, Kukull WA, Larson EB, Manly JJ, Alzheimer's Disease Genetics Consortium, Haines JL, Mayeux R, Pericak-Vance MA, Schellenberg GD, Lunetta KL, Farrer LA. Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. Alzheimers Dement. 2017 Feb;13(2):119-129. Epub 2016 Oct 20 PubMed.
12. Cukier HN, Kunkle BW, Vardarajan BN, Rolati S, Hamilton-Nelson KL, Kohli MA, Whitehead PL, Dombroski BA, Van Booven D, Lang R, Dykxhoorn DM, Farrer LA, Cuccaro ML, Vance JM, Gilbert JR, Beecham GW, Martin ER, Carney RM, Mayeux R, Schellenberg GD, Byrd GS, Haines JL, Pericak-Vance MA, Alzheimer's Disease Genetics Consortium. ABCA7 frameshift deletion associated with Alzheimer disease in African Americans. Neurol Genet. 2016 Jun;2(3):e79. Epub 2016 May 17 PubMed.
13. Kunkle BW, Carney RM, Kohli MA, Naj AC, Hamilton-Nelson KL, Whitehead PL, Wang L, Lang R, Cuccaro ML, Vance JM, Byrd GS, Beecham GW, Gilbert JR, Martin ER, Haines JL, Pericak-Vance MA. Targeted sequencing of ABCA7 identifies splicing, stop-gain and intronic risk variants for Alzheimer disease. Neurosci Lett. 2017 May 10;649:124-129. Epub 2017 Apr 8 PubMed.
14. 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.
15. Evans DA, Bennett DA, Wilson RS, Bienias JL, Morris MC, Scherr PA, Hebert LE, Aggarwal N, Beckett LA, Joglekar R, Berry-Kravis E, Schneider J. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003 Feb;60(2):185-9. PubMed.
16. Kang SS, Ebbert MT, Baker KE, Cook C, Wang X, Sens JP, Kocher JP, Petrucelli L, Fryer JD. Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J Exp Med. 2018 Sep 3;215(9):2235-2245. Epub 2018 Aug 6 PubMed.
17. Gilsanz P, Mayeda ER, Glymour MM, Quesenberry CP, Whitmer RA. Association Between Birth in a High Stroke Mortality State, Race, and Risk of Dementia. JAMA Neurol. 2017 Sep 1;74(9):1056-1062. PubMed.
18. Gilsanz P, Mayeda ER, Glymour MM, Quesenberry CP Jr, Mungas D, DeCarli CS, Whitmer RA. Birth in High Infant Mortality States and Dementia Risk in a Cohort of Elderly African American and White Health Care Members. Alzheimer Dis Assoc Disord. 2018 Aug 13; PubMed.

External Citations

1. Frey et al., 2012

Further Reading

No Available Further Reading