Generalizability of blood-based biomarkers of Alzheimer's disease and related dementias in a multicultural cohort of older adults: The effect of adjustment for kidney function
Restricted accessResearch articleFirst published online April, 2026
Generalizability of blood-based biomarkers of Alzheimer's disease and related dementias in a multicultural cohort of older adults: The effect of adjustment for kidney function
Interpreting blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) in a multicultural cohort is complicated by inconsistent evidence on racial differences. Kidney function, which varies by race and influences biomarker levels, is often overlooked, potentially contributing to these inconsistencies.
Objective
To characterize racial differences in plasma levels of ADRD biomarkers after adjusting for comorbidities and assessed the impact of estimated glomerular filtration rate (eGFR) adjustment using either race-specific or race-neutral equations.
Methods
Data from the Einstein Aging Study, a multicultural cohort of older adults, included plasma biomarkers (Aβ40, Aβ42, pTau181, NfL, GFAP). Linear regression models evaluated racial differences in AD plasma biomarkers, adjusting for age, sex, body mass index, kidney function assessed via race-adjusted (eGFR-ASR) and race-neutral (eGFR-AS) equations, comorbidities (e.g., diabetes, hypertension, cardiovascular disease), and APOE ε4 carrier status.
Results
Among 269 participants, Black participants had lower plasma levels of Aβ40 (p = 0.004), Aβ42 (p = 0.002), and NfL (p = 0.022) compared to White participants. We observed modest variation in the magnitude of racial differences depending on the method used to adjust for kidney function. However, race differences remained after adjusting for comorbidities or APOE ε4 carrier status.
Conclusions
Observed racial differences in ADRD biomarkers remain unexplained by kidney function, comorbidities or APOE ε4 carrier status. Future research focusing on associations between blood-based biomarkers and gold standards of brain pathology in multicultural cohorts are essential to advance the usability of blood biomarkers.
JackCRJrBennettDABlennowK, et al.NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement2018; 14: 535–562.
2.
GrøntvedtGRLauridsenCBergeG, et al.The amyloid, tau, and neurodegeneration (A/T/N) classification applied to a clinical research cohort with long-term follow-up. J Alzheimers Dis2020; 74: 829–837.
3.
LeuzyAMattsson-CarlgrenNPalmqvistS, et al.Blood-based biomarkers for Alzheimer’s disease. EMBO Mol Med2022; 14: e14408.
4.
TeunissenCEVerberkIMWThijssenEH, et al.Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol2022; 21: 66–77.
5.
KarikariTKAshtonNJBrinkmalmG, et al.Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility. Nat Rev Neurol2022; 18: 400–418.
6.
ChourakiVBeiserAYounkinL, et al.Plasma amyloid-β and risk of Alzheimer’s disease in the Framingham Heart Study. Alzheimers Dement2015; 11: 249–257.e1.
7.
GiauVVBagyinszkyEAnSSA. Potential fluid biomarkers for the diagnosis of mild cognitive impairment. Int J Mol Sci2019; 20: 4149.
8.
QuYMaY-HHuangY-Y, et al.Blood biomarkers for the diagnosis of amnestic mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. Neurosci Biobehav Rev2021; 128: 479–486.
9.
ChenY-RLiangC-SChuH, et al.Diagnostic accuracy of blood biomarkers for Alzheimer’s disease and amnestic mild cognitive impairment: a meta-analysis. Ageing Res Rev2021; 71: 101446.
10.
Milà-AlomàMAshtonNJShekariM, et al.Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease. Nat Med2022; 28: 1797–1801.
11.
HanssonOZetterbergHVanmechelenE, et al.Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer’s disease in patients with mild cognitive impairment. Neurobiol Aging2010; 31: 357–367.
12.
WinstonCNGoetzlEJAkersJC, et al.Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amst)2016; 3: 63–72.
13.
KorolevIOSymondsLLBozokiAC, et al.Predicting progression from mild cognitive impairment to Alzheimer’s dementia using clinical, MRI, and plasma biomarkers via probabilistic pattern classification. PLoS One2016; 11: e0138866.
14.
BlennowKDe MeyerGHanssonO, et al.Evolution of Abeta42 and Abeta40 levels and Abeta42/Abeta40 ratio in plasma during progression of Alzheimer’s disease: a multicenter assessment. J Nutr Health Aging2009; 13: 205–208.
15.
O’BryantSEPetersenMHallJ, et al.Medical comorbidities and ethnicity impact plasma Alzheimer’s disease biomarkers: important considerations for clinical trials and practice. Alzheimers Dement2023; 19: 36–43.
16.
BrickmanAMManlyJJHonigLS, et al.Plasma p-tau181, p-tau217, and other blood-based Alzheimer’s disease biomarkers in a multi-ethnic, community study. Alzheimers Dement2021; 17: 1353–1364.
17.
HallJRPetersenMJohnsonL, et al.Characterizing plasma biomarkers of Alzheimer’s in a diverse community-based cohort: a cross-sectional study of the HAB-HD cohort. Front Neurol2022; 13: 871947.
18.
Krell-RoeschJZanilettiISyrjanenJA, et al.Plasma-derived biomarkers of Alzheimer’s disease and neuropsychiatric symptoms: a community-based study. Alzheimers Dement (Amst)2023; 15: e12461.
19.
MattssonNRosénEHanssonO, et al.Age and diagnostic performance of Alzheimer disease CSF biomarkers. Neurology2012; 78: 468–476.
20.
DukartJMuellerKVillringerA, et al.Relationship between imaging biomarkers, age, progression and symptom severity in Alzheimer’s disease. Neuroimage Clin2013; 3: 84–94.
21.
MielkeMM. Consideration of sex differences in the measurement and interpretation of Alzheimer’s disease-related biofluid-based biomarkers. J Appl Lab Med2020; 5: 158–169.
22.
Vila-CastelarCLoperaFZetterbergH, et al.Sex differences in blood-based biomarkers in individuals with autosomal dominant Alzheimer’s disease. Alzheimers Dement2021; 17: e055011.
23.
TsikniaAAEdlandSDSundermannEE, et al.Sex differences in plasma p-tau181 associations with Alzheimer’s disease biomarkers, cognitive decline, and clinical progression. Mol Psychiatry2022; 27: 4314–4322.
24.
GleasonCEZuelsdorffMGoodingDC, et al.Alzheimer’s disease biomarkers in Black and non-Hispanic White cohorts: a contextualized review of the evidence. Alzheimers Dement2022; 18: 1545–1564.
25.
MatthewsKAXuWGagliotiAH, et al.Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015–2060) in adults aged ≥65 years. Alzheimers Dement2019; 15: 17–24.
26.
LimUWangSParkS-Y, et al.Risk of Alzheimer’s disease and related dementia by sex and race/ethnicity: the Multiethnic Cohort Study. Alzheimers Dement2022; 18: 1625–1634.
27.
HajjarIYangZOkaforM, et al.Association of plasma and cerebrospinal fluid Alzheimer disease biomarkers with race and the role of genetic ancestry, vascular comorbidities, and neighborhood factors. JAMA Netw Open2022; 5: e2235068.
28.
XiongCLuoJWolkDA, et al.Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals. Nat Commun2024; 15: 5539.
29.
SchindlerSEKarikariTKAshtonNJ, et al.Effect of race on prediction of brain amyloidosis by plasma Aβ42/Aβ40, phosphorylated tau, and neurofilament light. Neurology2022; 99: e245–e257.
30.
RajanKBMcAninchEAAggarwalNT, et al.Longitudinal changes in blood biomarkers of clinical Alzheimer disease in a biracial population sample. Neurology2023; 100: e874–e883.
31.
GuYHonigLSKangMS, et al.Risk of Alzheimer’s disease is associated with longitudinal changes in plasma biomarkers in the multi-ethnic Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP) cohort. Alzheimers Dement2024; 20: 1988–1999.
32.
RamananVKGraff-RadfordJSyrjanenJ, et al.Association of plasma biomarkers of Alzheimer disease with cognition and medical comorbidities in a biracial cohort. Neurology2023; 101: e1402–e1411.
33.
MielkeMM. Sex and gender differences in Alzheimer’s disease dementia. Psychiatr Times2018; 35: 14–17.
34.
MielkeMM. Interpreting blood-based biomarker results in heterogeneous populations with multiple co-morbidities. Alzheimers Dement2022; 18: e066904.
35.
StockerHBeyerLTraresK, et al.Association of kidney function with development of Alzheimer disease and other dementias and dementia-related blood biomarkers. JAMA Netw Open2023; 6: e2252387.
36.
DittrichAAshtonNJZetterbergH, et al.Association of chronic kidney disease with plasma NfL and other biomarkers of neurodegeneration. Neurology2023; 101: e277–e288.
37.
ZhangBZhangCWangY, et al.Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer’s disease. Front Aging Neurosci2023; 15: 1150510.
38.
VerdeFMiloneIDubiniA, et al.Influence of kidney function and CSF/serum albumin ratio on plasma Aβ42 and Aβ40 levels measured on a fully automated platform in patients with Alzheimer’s disease. Neurol Sci2023; 44: 3287–3290.
39.
PeraltaCAKatzRDeBoerI, et al.Racial and ethnic differences in kidney function decline among persons without chronic kidney disease. J Am Soc Nephrol2011; 22: 1327.
40.
VartPGansevoortRTJoostenMM, et al.Socioeconomic disparities in chronic kidney disease: a systematic review and meta-analysis. Am J Prev Med2015; 48: 580–592.
41.
KjaergaardDSimonsenAHWaldemarG, et al.Ethnic and racial influences on blood biomarkers for Alzheimer’s disease: a systematic review. J Alzheimers Dis2025; 103: 81–91.
42.
InkerLAEneanyaNDCoreshJ, et al.New creatinine-and cystatin C–based equations to estimate GFR without race. N Engl J Med2021; 385: 1737–1749.
43.
LeveyASStevensLASchmidCH, et al.A new equation to estimate glomerular filtration rate. Ann Intern Med2009; 150: 604–612.
44.
LeveyASTitanSMPoweNR, et al.Kidney disease, race, and GFR estimation. Clin J Am Soc Nephrol2020; 15: 1203–1212.
45.
PoggioEDWangXGreeneT, et al.Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease. J Am Soc Nephrol2005; 16: 459–466.
46.
AssariS. Racial disparities in chronic kidney diseases in the United States; a pressing public health challenge with social, behavioral and medical causes. J Nephropharmacology2015; 5: 4–6.
47.
NorrisKMehrotraRNissensonAR. Racial differences in mortality and end-stage renal disease. Am J Kidney Dis2008; 52: 205–208.
48.
GutiérrezOMSangYGramsME, et al.Association of estimated GFR calculated using race-free equations with kidney failure and mortality by Black vs non-Black race. JAMA2022; 327: 2306–2316.
49.
MarzinkeMAGreeneDNBossuytPM, et al.Limited evidence for use of a black race modifier in eGFR calculations: a systematic review. Clin Chem2022; 68: 521–533.
50.
DiaoJAPoweNRManraiAK. Race-free equations for eGFR: comparing effects on CKD classification. J Am Soc Nephrol2021; 32: 1868.
51.
Pichet BinetteAJanelidzeSCullenN, et al.Confounding factors of Alzheimer’s disease plasma biomarkers and their impact on clinical performance. Alzheimers Dement2023; 19: 1403–1414.
52.
ArvanitakisZLucasJAYounkinLH, et al.Serum creatinine levels correlate with plasma amyloid β protein. Alzheimer Dis Assoc Disord2002; 16: 187.
53.
JanelidzeSBarthélemyNRHeY, et al.Mitigating the associations of kidney dysfunction with blood biomarkers of Alzheimer disease by using phosphorylated tau to total tau ratios. JAMA Neurol2023; 80: 516–522.
54.
BlankenshipAEYokshLKueckPJ, et al.Changes in Alzheimer’s disease blood biomarkers in kidney failure before and after kidney transplant. Alzheimers Dement (Amst)2024; 16: e12614.
55.
GaspariniFVallettaMVetranoDL, et al.Kidney function, Alzheimer disease blood biomarkers, and dementia risk in community-dwelling older adults. Neurology2026; 106: e214446.
56.
KjaergaardDSimonsenAHWaldemarG, et al.Ethnic and racial influences on blood biomarkers for Alzheimer’s disease: a systematic review. J Alzheimers Dis2025; 103: 81–91.
57.
SyrjanenJACampbellMRAlgeciras-SchimnichA, et al.Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities. Alzheimers Dement2022; 18: 1128–1140.
58.
RaberJHuangYAshfordJW. Apoe genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging2004; 25: 641–650.
59.
BeydounMAWeissJBeydounHA, et al.Race, APOE genotypes, and cognitive decline among middle-aged urban adults. Alzheimers Res Ther2021; 13: 120.
60.
KatzMJLiptonRBHallCB, et al.Age and sex specific prevalence and incidence of mild cognitive impairment, dementia and Alzheimer’s dementia in Blacks and Whites: a report from the Einstein Aging Study. Alzheimer Dis Assoc Disord2012; 26: 335–343.
61.
KatzMJWangCNesterCO, et al.T-MoCA: a valid phone screen for cognitive impairment in diverse community samples. Alzheimers Dement (Amst)2021; 13: e12144.
62.
LiptonRKatzMKuslanskyG, et al.Screening for dementia by telephone using the memory impairment screen. J Am Geriatr Soc2003; 51: 1382–1390.
63.
JakAJBondiMWDelano-WoodL, et al.Quantification of five neuropsychological approaches to defining mild cognitive impairment. Am J Geriatr Psychiatry2009; 17: 368–375.
64.
BondiMWEdmondsECJakAJ, et al.Neuropsychological criteria for mild cognitive impairment improves diagnostic precision, biomarker associations, and progression rates. J Alzheimers Dis2014; 42: 275–289.
65.
SoldanAPettigrewCWangJ, et al.Blood-based biomarkers and risk of MCI symptom onset over the short and long-term. Alzheimers Dement2024; 20: e091476.
66.
KarikariTKPascoalTAAshtonNJ, et al.Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol2020; 19: 422–433.
67.
CullenNCLeuzyAJanelidzeS, et al.Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations. Nat Commun2021; 12: 3555.
68.
SeppäläTTHerukkaS-KHänninenT, et al.Plasma Abeta42 and Abeta40 as markers of cognitive change in follow-up: a prospective, longitudinal, population-based cohort study. J Neurol Neurosurg Psychiatry2010; 81: 1123–1127.
69.
JanelidzeSStomrudEPalmqvistS, et al.Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci Rep2016; 6: 26801.
70.
LeveyASStevensLASchmidCH, et al.A new equation to estimate glomerular filtration rate. Ann Intern Med2009; 150: 604–612.
71.
LennonJCAitaSLBeneVAD, et al.Black and White individuals differ in dementia prevalence, risk factors, and symptomatic presentation. Alzheimers Dement2022; 18: 1461–1471.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
