15 Feb 2025

Although efforts to identify biomarkers for Alzheimer's disease are advancing rapidly, many still struggle to obtain information from populations other than non-Hispanic white people. At the Human Amyloid Imaging (HAI) conference, held January 15-17 in San Juan, Puerto Rico, researchers presented new data suggesting that clinical staging frameworks and standard biomarker sets might not accurately reflect disease progression in all racial and ethnic groups.

Black and Hispanic people are more likely to develop all-cause dementia than their white counterparts, but have historically made up less than 5 percent of clinical trial participants. In his keynote talk at HAI, Sid O’Bryant, University of North Texas Health Science Center, Fort Worth, said this disparity partly stems from recruitment challenges and unequal access to healthcare facilities. But it is changing, and emerging data indeed points to some biological differences in the way dementia develops in different populations.

One recent analysis from the screening and recruitment data of the ongoing AHEAD lecanemab secondary prevention trial found that black people were less likely to have brain amyloid than non-Hispanic white people with the same amount of cognitive impairment. This means that they could not be included in AHEAD, which, as an amyloid-removal trial, had a minimum amyloid threshold as an inclusion criteria (Nov 2024 news).

Such findings challenge scientists’ general understanding of the etiology and features of Alzheimer's disease and related dementias, O’Bryant believes. For instance, most of the data used to design the amyloid-tau-neurodegeneration classification (ATN) framework came from the Alzheimer's Disease Neuroimaging Study, which included more than 90 percent white people in its earliest iteration, and from the Mayo Clinic Study of Aging, which started in 2004 in Minnesota’s Olmstead county and is 97 percent white (Lim et al., 2023; Schwarz et al., 2025). “How these biomarkers look across a broader range of populations is simply unknown,” O’Bryant said.

More recent cohort extension studies, such as the Health and Aging Brain Study’s Health Disparities (HABS-HD) project that O’Bryant directs, have statistical power to begin examining disease progression in diverse populations (Nov 2023 conference news). In one presentation at HAI, Annie Cohen, University of Pittsburgh School of Medicine, showed one of the first attempts to quantify these differences on a large scale using data from the HABS-HD cohort. Her group collected MRIs, tau, and amyloid PET scans from 1,082 non-Hispanic white, 1,079 Mexican American and 605 non-Hispanic black participants who had varying levels of cognitive impairment.

The researchers modelled how Aβ, tau, and neurodegeneration progressed over time in each of these groups. In essence, the stages of white HABS-HD participants’ disease fit the ATN framework—amyloid PET became positive before tau PET or before MRI showed significant hippocampal neurodegeneration. In contrast, in both black and Hispanic cohorts, all three pathologies became detectable at the same time. They also progressed at around the same rate, whereas in whites the three pathologies progressed at different rates. “As we get into studying the individuals who've been historically excluded from research for a variety of reasons, we have to be more careful in interpreting how well [the ATN] framework will work,” Cohen told Alzforum.

Graded on a Curve. Amyloid accumulation (blue) precedes other pathologies in non-Hispanic whites (left columns). Plaques, tangles (yellow), hippocampal atrophy (pink), and white-matter damage (purple) occur simultaneously in Mexican-American (center) and non-Hispanic black (right) populations. Left set of 6 graphs represents ApoE4 noncarriers; right set, carriers. (Courtesy of Annie Cohen.)

Reisa Sperling, also at Harvard, who co-directs the Harvard Aging Brain Study, finds the Texas HABS-HD data compelling in showing that amyloid can’t be the only target when studying diverse populations with dementia. “We have to go after multiple processes that contribute to cognitive decline,” she told Alzforum. Future trials, she said, should study combinations of factors across diverse populations. An example is the Alzheimer Plasma Extension observational study (APEX) which studies biomarkers, cognition and the social determinants of health in people who didn’t qualify for the AHEAD lecanemab trial. Sperling said that 54 percent of the people in APEX are racial minorities.

Cohen’s group also confirmed previous findings that while carrying the ApoE4 allele significantly increased Alzheimer's risk in non-Hispanic white people, the allele had little effect among black and Hispanic people. “It may be that there are other social determinants of health, other factors that increase risk so much it washes out ApoE4,” she told Alzforum.

Lea Grinberg, University of California, San Francisco, said that while the HABS-HD study doesn’t invalidate ATN staging, it does suggest that broader criteria might be needed. Suzanne Schindler, Washington University, St. Louis, told Alzforum that clinicians might conflate Alzheimer's with non-AD dementias that are more common in non-white populations. “We're applying an Alzheimer's framework to people who don't have Alzheimer's disease, and that's why things aren't lining up,” she said. Emerging data on proteomics may help improve such diagnoses, she said.

Cohen encouraged researchers to look at biomarker patterns within racial minority groups with dementia, rather than only trying to compare diverse cohorts against white cohorts.

In one poster at HAI, for example, Lindsey Kuchenbecker and senior author Minerva Carrasquillo, Mayo Clinic, Jacksonville, Florida, analyzed plasma biomarkers in the Florida Consortium of African American Alzheimer’s Disease Studies (FCA3DS). The purpose, Carrasquillo said, was to find proteins that are not necessarily associated with tau or amyloid aggregation, but could identify disease processes such as immune response or vascular disease that might be particularly relevant in non-white populations. “We have to do a better job at studying the full spectrum of risk factors in these underrepresented populations so that we can have a better understanding of the biology underlying the disease,” she told Alzforum.

Using the SomaScan 7k assay, which measures levels of 7,300 plasma proteins, Kuchenbecker and colleagues compared the blood proteomes of 145 cognitively unimpaired people with 183 who had been clinically diagnosed with Alzheimer's dementia. No PET or fluid testing was used to confirm their diagnoses. A machine learning algorithm bubbled up 32 unique proteins that distinguished the two groups.

Fourteen of these had been previously linked with Alzheimer's pathology in some way. Some were linked to amyloid or tau pathology, including the protein-folding markers SFRP1 and SPON1. Others were associated with neurodegeneration, such as synaptic dysfunction marker NPTXR, the inflammation-related protein IGFBP-2, and a synaptic vesicle protein called CPLX2 that was spotted in plasma seven years prior to symptom onset in autosomal-dominant AD.  

Eighteen others represented novel potential markers. They include the cytokine CCL25, which has been associated with poorer performance on cognitive tests among MCI patients (see also Ferguson et al., 2020), the chemokine CCL22, which is made by dendritic cells and macrophages and has been reported in several neuroinflammatory conditions, and TAGLN, which affects cell migration and could be associated with cerebrovascular dysfunction (e.g., Gomez et al., 2025). 

Blood Ties. Plasma samples from a black cohort revealed 98 proteins that increased in clinically diagnosed AD and 22 that decreased. Some had been previously associated with neuroinflammation and vascular degeneration, others had not. (Kuchenbecker et al., bioRxiv 2024).

The researchers replicated their findings in the Accelerating Medicines Project’s AD Diverse Cohorts’ postmortem brain proteomics dataset—an extension of the AMP-AD brain collection project. In these proteomes, the 32 proteins Carrasquillo’s group found in the FCA3DS plasma samples distinguished autopsy-confirmed Alzheimer's cases from controls with 91percent accuracy.

Kuchenbecker acknowledged that these disease end-stage brain proteins might not have been present in the plasma since blood samples were not available, but said the predictive power of the FCA3DS’s initial blood dataset’s suggests these proteins can distinguish between AD and controls, not just dementia cases diagnosed as AD. The scientists uploaded a manuscript to bioRxiv last July (Kuchenbecker et al., 2024). They are now looking for these hits in other ADRC cohorts to see whether they occur in non-Hispanic white and other diverse populations

Schindler would like to see plasma p-tau217 analyzed in this cohort. It is not included in the SomaScan 7k assay used in the study. “It's great to look at stuff in addition to p-tau217, but it's so important that leaving it out just doesn't make sense anymore,” she said.

Nevertheless, Schindler is excited to see statistically valid findings emerging from HABS-HD and other diverse cohorts. “For a while I was skeptical that there would be racial and ethnic differences because Alzheimer's is the same no matter the color of your skin,” she said. That quantifiable differences exist, she said, “has an important impact on diagnostics and treatments.”

“These studies highlight the importance of studying representative cohorts that mirror the racial and ethnic diversity of older adults at risk for cognitive impairment. The findings strongly suggest that late-onset dementia may involve distinct biological pathways and upstream drivers, depending on racial and ethnic background,” wrote Gil Rabinovici, University of California, San Francisco. “Better understanding the social determinants that drive these findings is therefore a critical element of our overall strategy to prevent dementia.”—Sara Reardon

Sara Reardon is a freelance writer in Bozeman, Montana.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Biomarkers Suggest Black and Hispanic People Less Likely to Have Amyloid 20 Nov 2024
2. To Recruit for Diverse Alzheimer Trials, Go to the People 5 Nov 2023

Paper Citations

1. Lim AC, Barnes LL, Weissberger GH, Lamar M, Nguyen AL, Fenton L, Herrera J, Han SD. Quantification of race/ethnicity representation in Alzheimer's disease neuroimaging research in the USA: a systematic review. Commun Med (Lond). 2023 Jul 25;3(1):101. PubMed.
2. Schwarz CG, Kremers WK, Prakaashana CM, Przybelski SA, Christenson LR, Wiliams JM, Gunter JL, Senjem ML, Arani A, Reid RI, Machulda MM, Fields JA, Lowe VJ, Kantarci K, Graff‐Radford J, Vemuri P, Petersen RC, Knopman DS, Jack CR Jr. A Large Public Release of Clinical and Imaging Data from the Mayo Clinic Study of Aging. Alzheimers Dement. 2025 Jan 9;20(Suppl 9):e093966. Alzheimer's & Dementia
3. Ferguson SA, Varma V, Sloper D, Panos JJ, Sarkar S. Increased inflammation in BA21 brain tissue from African Americans with Alzheimer's disease. Metab Brain Dis. 2020 Jan;35(1):121-133. Epub 2019 Dec 10 PubMed.
4. Gomez GT, Sathyan S, Chen J, Fornage M, Schlosser P, Peng Z, Cordon J, Palta P, Sullivan KJ, Tin A, Windham BG, Gottesman RF, Barzilai N, Milman S, Verghese J, Coresh J, Walker KA. Plasma proteomic characterization of motoric cognitive risk and mild cognitive impairment. Alzheimers Dement. 2025 Jan 30;:e14429. Epub 2025 Jan 30 PubMed.
5. Kuchenbecker LA, Thompson KJ, Hurst CD, Opdenbosch BM, Heckman MG, Reddy JS, Nguyen T, Casellas HL, Sotelo KD, Reddy DJ, Lucas JA, Day GS, Willis FB, Graff-Radford N, Ertekin-Taner N, Kalari KR, Carrasquillo MM. Nomination of a novel plasma protein biomarker panel capable of classifying Alzheimer's disease dementia with high accuracy in an African American cohort. bioRxiv. 2024 Jul 29; PubMed.

Further Reading

News

1. Biomarkers Suggest Black and Hispanic People Less Likely to Have Amyloid 20 Nov 2024
2. From St. Louis to Boston, Scientists Grapple with Ethnoracial Divide in AD Biomarkers 5 Nov 2023
3. To Recruit for Diverse Alzheimer Trials, Go to the People 5 Nov 2023