Restricted accessResearch articleFirst published online 2026-3
Independent associations of phosphorylated tau181 and neurofilament light with cognitive outcomes in the Health and Aging Brain Study–Health Disparities (HABS-HD)
The extent to which plasma biomarkers of Alzheimer's disease and neurodegeneration capture domain-specific cognitive performance across diverse populations remains unclear.
Objective
To determine whether plasma phosphorylated tau181 (p-tau181) and neurofilament light (NfL) are independently associated with cognitive domains, and whether associations differ across non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic participants.
Methods
We analyzed 3023 community-dwelling older adults from the Health and Aging Brain Study–Health Disparities (38.4% NHW, 22.6% NHW, 38.9% Hispanic). We used linear regressions to test associations between plasma biomarkers and cognitive domains (memory, executive function, processing speed, language), adjusting for age, sex, education, and apolipoprotein ε4 carriership. We fit models including both p-tau181 and NfL to assess their independent associations, evaluate biomarker × racial/ethnic interactions, and test p-tau181 × NfL interactions within each racial/ethnic group.
Results
Among NHW participants, higher p-tau181 and NfL were associated with poorer memory, executive function, processing speed, and language. In NHB participants, p-tau181 was associated with memory, showed attenuated associations for language, and demonstrated similar associations with executive function and processing speed as observed in NHW participants. In Hispanic participants, p-tau181 was associated with memory and processing speed but was nonsignificant for executive function and language, and NfL showed significant but attenuated associations across all domains. Higher p-tau181 and NfL were jointly associated with slower processing speed only in NHW and NHB participants.
Conclusions
Plasma p-tau181 and NfL were associated with multiple cognitive domains, with the strongest effects in NHW participants and attenuated associations in NHB and Hispanic individuals.
RabinoviciGDGatsonisCApgarC, et al.Association of Amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia. JAMA2019; 321: 1286.
8.
JackCRAndrewsJSBeachTG, et al.Revised criteria for diagnosis and staging of Alzheimer’s disease: alzheimer’s Association Workgroup. Alzheimers Dement2024; 20: 5143–5169.
9.
DuboisBVillainNSchneiderL, et al.Alzheimer disease as a clinical-biological construct—an international working group recommendation. JAMA Neurol2024; 81: 1304–1311.
10.
AshtonNJJanelidzeSMattsson-CarlgrenN, et al.Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring. Nat Med2022; 28: 2555–2562.
11.
HanssonOBlennowKZetterbergH, et al.Blood biomarkers for Alzheimer’s disease in clinical practice and trials. Nat Aging2023; 3: 506–519.
12.
PalmqvistSWarmenhovenNAnastasiF, et al.Plasma phospho-tau217 for Alzheimer’s disease diagnosis in primary and secondary care using a fully automated platform. Nat Med2025; 31: 2036–2043.
13.
AnastasiFFernández-LebreroAAshtonNJ, et al.A head-to-head comparison of plasma biomarkers to detect Alzheimer’s disease in a memory clinic. Alzheimers Dement2025; 21: e14609.
14.
TherriaultJBrumWSTrudelL, et al.Blood phosphorylated tau for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol2025; 24: 740–752.
15.
OlssonBLautnerRAndreassonU, et al.CSF And blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol2016; 15: 673–684.
16.
ZhaoYXinYMengS, et al.Neurofilament light chain protein in neurodegenerative dementia: a systematic review and network meta-analysis. Neurosci Biobehav Rev2019; 102: 123–138.
17.
CronjéHTLiuXOddenMC, et al.Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: the cardiovascular health study. Alzheimers Dement2023; 19: 5672–5680.
18.
FohnerAEBartzTMTracyRP, et al.Association of serum neurofilament light chain concentration and MRI findings in older adults: the Cardiovascular Health Study. Neurology2022; 98: e903–e911.
19.
MattssonNAndreassonUZetterbergH, et al.Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol2017; 74: 557.
20.
JackCRKnopmanDSJagustWJ, et al.Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol2013; 12: 207–216.
21.
DuboisBHampelHFeldmanHH, et al.Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimers Dement2016; 12: 292–323.
22.
BellenguezCKüçükaliFJansenIE, et al.New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet2022; 54: 412–436.
23.
KarikariTK. Blood tests for Alzheimer’s disease: increasing efforts to expand and diversify research participation is critical for widespread validation and acceptance. J Alzheimers Dis2022; 90: 967–974.
24.
SewellKROberlinLEKarikariTK, et al.Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits. Alzheimers Dement2025; 21: e14619.
25.
KimJKAnwarMGuptaA, et al.Association of blood-based neurodegenerative biomarkers with cognitive functioning and dementia in India (LASI-DAD) and the United States (HRS). Am J Epidemiol2025; 194: 3705–3713.
26.
YakoubYAshtonNJStrikwerda-BrownC, et al.Longitudinal blood biomarker trajectories in preclinical Alzheimer’s disease. Alzheimers Dement2023; 19: 5620–5631.
27.
ChatterjeePGoozeeKSohrabiHR, et al. Association of plasma neurofilament light chain with neocortical amyloid-β load and cognitive performance in cognitively normal elderly participants. J Alzheimers Dis2018; 63: 479–487.
28.
CullenN CLeuzyAJanelidzeS, et al. Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations. Nat Commun2021; 12: 3555.
29.
KhalilMPirpamerLHoferE, et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun2020; 11: 812.
30.
Mattsson-CarlgrenNSalvadóGAshtonNJ, et al. Prediction of longitudinal cognitive decline in preclinical Alzheimer disease using plasma biomarkers. JAMA Neurol2023; 80: 360–369.
31.
SimrénJLeuzyAKarikariTK, et al. The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer’s disease. Alzheimers Dement2021; 17: 1145–1156.
32.
TsaiC-LLiangC-SLeeJ-T, et al. Associations between plasma biomarkers and cognition in patients with Alzheimer’s disease and amnestic mild cognitive impairment: a cross-sectional and longitudinal study. J Clin Med2019; 8: 1893.
33.
ZhangYFerreiraPCLJacobsenE, et al. Association of plasma biomarkers of Alzheimer’s disease and related disor- ders with cognition and cognitive decline: the MYHAT population-based study. Alzheimers Dement2024; 20: 4199–4211.
34.
Garcia-EscobarGManeroRMFernández-LebreroA, et al.Blood biomarkers of Alzheimer’s disease and cognition: a literature review. Biomolecules2024; 14: 93.
35.
O’BryantSEJohnsonLABarberRC, et al.The Health & Aging Brain among Latino Elders (HABLE) study methods and participant characteristics. Alzheimers Dement (Amst)2021; 13: e12202.
36.
O’BryantSEPetersenMHallJ, et al.APOEɛ4 genotype is related to brain amyloid among Mexican Americans in the HABS-HD Study. Front Neurol2022; 13: 834685.
37.
CorderEHSaundersAMStrittmatterWJ, et al.Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science1993; 261: 921–923.
38.
SandoSBMelquistSCannonA, et al.APOE Epsilon 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurol2008; 8: 9.
39.
AbdullahLZhangFHallJ, et al.Neurofilament light and cognition in community-dwelling non-Hispanic Blacks. J Alzheimers Dis2024; 102: 60–66.
40.
O’BryantSPetersenMHallJ, et al.Characterizing plasma NfL in a community-dwelling multi-ethnic cohort: results from the HABLE study. Alzheimers Dement2022; 18: 240–250.
41.
O’BryantSEPetersenMHallJR, et al.Plasma biomarkers of Alzheimer’s disease are associated with physical functioning outcomes among cognitively normal adults in the multiethnic HABS-HD Cohort. J Gerontol A Biol Sci Med Sci2023; 78: 9–15.
42.
O’BryantSEZhangFPetersenM, et al.A blood screening tool for detecting mild cognitive impairment and Alzheimer’s disease among community-dwelling Mexican Americans and non-Hispanic Whites: a method for increasing representation of diverse populations in clinical research. Alzheimers Dement2022; 18: 77–87.
43.
O’BryantSEZhangFPetersenM, et al.A blood screening tool for detecting mild cognitive impairment and Alzheimer’s disease among community-dwelling Mexican Americans and non-Hispanic Whites: a method for increasing representation of diverse populations in clinical research. Alzheimers Dement2022; 18: 77–87.
44.
TimsinaJAliMDoA, et al.Harmonization of CSF and imaging biomarkers in Alzheimer’s disease: need and practical applications for genetics studies and preclinical classification. Neurobiol Dis2024; 190: 106373.
45.
PetersenMEZhouZHallJR, et al.Health and Aging Brain Study-Health Disparities (HABS-HD) methods and partner characteristics. Alzheimers Dement (N Y)2025; 11: e70140.
46.
McKhannGDrachmanDFolsteinM, et al.Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology1984; 34: 939–939.
47.
AbdullahLBZhouZAllieyNA, et al.Low premorbid IQ may exacerbate the cognitive effects of apolipoprotein ɛ4 (APOEɛ4): a multi-ethnic cross-sectional study from HABS-HD. Front Neurol2025; 16: 1627525.
48.
ChenS-DHuangY-YShenX-N, et al.Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer’s disease. Transl Psychiatry2021; 11: 356.
49.
JanelidzeSMattssonNPalmqvistS, et al.Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med2020; 26: 379–386.
50.
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.
51.
LussierFZBenedetALTherriaultJ, et al.Plasma levels of phosphorylated tau 181 are associated with cerebral metabolic dysfunction in cognitively impaired and amyloid-positive individuals. Brain Commun2021; 3: fcab073.
52.
MazzeoSIngannatoAGiacomucciG, et al.Plasma neurofilament light chain predicts Alzheimer’s disease in patients with subjective cognitive decline and mild cognitive impairment: a cross-sectional and longitudinal study. Eur J Neurol2023; 31: e16089.
53.
ThomasKSpinPSirN, et al.Neurofilament light (NfL) chain levels predict clinical decline in Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis Rep2025; 9: 25424823251379878.
54.
SewellKROberlinLEKarikariTK, et al.Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits. Alzheimers Dement2025; 21: e14619.
55.
ZhangYFerreiraPCLJacobsenE, et al.Association of plasma biomarkers of Alzheimer’s disease and related disorders with cognition and cognitive decline: the MYHAT population-based study. Alzheimers Dement2024; 20: 4199–4211.
56.
GaurAGallagherDHerrmannN, et al.Neurofilament light chain as a biomarker of global cognition in individuals with possible vascular mild cognitive impairment. J Geriatr Psychiatry Neurol2025; 38: 62–72.
57.
AlirezaeiZPourhanifehMHBorranS, et al.Neurofilament light chain as a biomarker, and correlation with magnetic resonance imaging in diagnosis of CNS-related disorders. Mol Neurobiol2020; 57: 469–491.
58.
GaetaniLBlennowKCalabresiP, et al.Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry2019; 90: 870–881.
59.
KhalilMTeunissenCEOttoM, et al.Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol2018; 14: 577–589.
60.
SchultzSAStrainJFAdedokunA, et al.Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer’s disease. Neurobiol Dis2020; 142: 104960.
61.
TangRBuchholzEDaleAM, et al.Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men. Alzheimers Res Ther2024; 16: 90.
62.
Lantero RodriguezJKarikariTKSuárez-CalvetM, et al.Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline. Acta Neuropathol2020; 140: 267–278.
63.
MielkeMMHagenCEXuJ, et al.Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement2018; 14: 989–997.
64.
MielkeMMAndersonMAshfordJW, et al.Recommendations for clinical implementation of blood-based biomarkers for Alzheimer’s disease. Alzheimers Dement2024; 20: 8216–8224.
65.
ChaoS-PLinW-CLuC-H, et al.Changes in plasma biomarkers differentiate clinical stages of Alzheimer’s disease using immunomagnetic reduction assays. J Alzheimers Dis2024; 102: 459–469.
66.
XiaoZWuXWuW, et al.Plasma biomarker profiles and the correlation with cognitive function across the clinical spectrum of Alzheimer’s disease. Alzheimers Res Ther2021; 13: 123.
67.
LabonteJSugarmanMAPettwayE, et al.Sex differences on tau, astrocytic, and neurodegenerative plasma biomarkers. J Alzheimers Dis2025; 105: 443–452.
68.
JackCRWisteHJAlgeciras-SchimnichA, et al.Predicting amyloid PET and tau PET stages with plasma biomarkers. Brain2023; 146: 2029–2044.
69.
DarkHEAnYDugganMR, et al.Alzheimer’s and neurodegenerative disease biomarkers in blood predict brain atrophy and cognitive decline. Alzheimers Res Ther2024; 16: 94.
70.
BucciMAlmkvistOBlumaM, et al.Profiling plasma biomarkers, particularly pTau217 and pTau217/Aβ42, and their relation to cognition in memory clinic patients. J Neurochem2025; 169: e70182.
71.
JackCRAndrewsJSBeachTG, et al.Revised criteria for diagnosis and staging of Alzheimer’s disease: alzheimer’s Association Workgroup. Alzheimers Dement2024; 20: 5143–5169.
72.
LeeEHKangSHKimYJ, et al.Relationships between medical comorbidities and plasma biomarkers of Alzheimer’s disease reflect increased pathological markers as well as biological variabilities. Alzheimers Dement2025; 20: e087856.
73.
ContrerasJAOrtegaNEEspejoK, et al.The effect of APOE4 on Alzheimer’s plasma biomarkers among Mexican Americans in the HABS-HD cohort. Alzheimers Res Ther2025; 17: 208.
74.
YangZShengJZhangQ, et al.Multimodal imaging markers of cognitive resilience and molecular mechanisms of brain resilience in Alzheimer’s disease. J Integr Neurosci2025; 24: 26584.
75.
Adkins-JacksonPBGeorgeKMBesserLM, et al.The structural and social determinants of Alzheimer’s disease related dementias. Alzheimers Dement2023; 19: 3171–3185.
76.
MaassALockhartSNHarrisonTM, et al.Entorhinal tau pathology, episodic memory decline, and neurodegeneration in aging. J Neurosci2018; 38: 530–543.
77.
GuoTLiASunP, et al.Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer’s disease. Mol Neurodegener2024; 19: 58.
78.
ShiDYeCLiA, et al.Presynaptic loss and axonal degeneration synergistically correlate with longitudinal neurodegeneration and cognitive decline. Alzheimers Dement2025; 21: e70080.
79.
AlvesGSSudoFKAlvesCEDO, et al.Diffusion tensor imaging studies in vascular disease: a review of the literature. Dement Neuropsychol2012; 6: 158–163.
80.
Atkinson-ClementCPintoSEusebioA, et al.Diffusion tensor imaging in Parkinson’s disease: review and meta-analysis. Neuroimage Clin2017; 16: 98–110.
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.
