Cerebrovascular risk factors, a group of conditions that reduce or disrupt blood flow to the brain, often occur with Alzheimer's disease (AD) and may contribute to the pathogenesis and cognitive decline. Hispanic individuals are at increased risk of vascular risk factors compared to non-Hispanic white counterparts.
Objective
We examined associations among vascular risk factors, including hypertension, diabetes, history of heart disease, and history of stroke, with plasma phosphorylated tau-181 (P-tau181) and cognition.
Methods
We pooled data from 2159 two cohorts of older Hispanic adults. Vascular risk factors were self-reported. Plasma P-tau181 was measured using standardized protocols. Linear regression and mediation models assessed associations among vascular risk, P-tau181, and global cognition, stratified by cognitive status.
Results
Overall, P-tau181 was significantly associated with vascular risk factors and inversely associated with cognitive function. However, vascular risk factors were not independently associated with cognition. Among cognitively unimpaired individuals, vascular risk factors mediated the association between P-tau181 and cognition, while in cognitively impaired individuals, P-tau181 was strongly and independently associated with cognition, without mediation by vascular risk factors.
Conclusions
Among elderly without dementia, vascular risk factors mediate the association between P-tau181 and cognition. However, among individuals with dementia there is no mediation, suggesting that the association between P-tau181 with dementia is independent of cerebrovascular pathology.
GuoJBrickmanAMManlyJJ, et al.Association of life’s simple 7 with incident dementia and its modification by the apolipoprotein E genotype. Alzheimers Dement2021; 17: 1905–1913.
2.
NordestgaardLTChristoffersenMFrikke-SchmidtR. Shared risk factors between dementia and atherosclerotic cardiovascular disease. Int J Mol Sci2022; 23: 9777.
3.
WebbAJSWerringDJ. New insights into cerebrovascular pathophysiology and hypertension. Stroke2022; 53: 1054–1064.
4.
WangYZhangHLiuL, et al.Cognitive function and cardiovascular health in the elderly: network analysis based on hypertension, diabetes, cerebrovascular disease, and coronary heart disease. Front Aging Neurosci2023; 15: 1229559.
5.
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.
6.
TeunissenCEVerberkIMWThijssenEH, et al.Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol2022; 21: 66–77.
7.
Mattsson-CarlgrenNSalvadoGAshtonNJ, et al.Prediction of longitudinal cognitive decline in preclinical Alzheimer disease using plasma biomarkers. JAMA Neurol2023; 80: 360–369.
8.
HonigLSKangMSLeeAJ, et al.Evaluation of plasma biomarkers for A/T/N classification of Alzheimer disease among adults of Caribbean hispanic ethnicity. JAMA Netw Open2023; 6: e238214.
9.
ImbimboBPWatlingMImbimboC, et al.Plasma ATN(I) classification and precision pharmacology in Alzheimer’s disease. Alzheimers Dement2023; 19: 4729–4734.
10.
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.
11.
VerberkIMWHendriksenHMAHartenAC, et al.Plasma amyloid is associated with the rate of cognitive decline in cognitively normal elderly: the SCIENCe project. Neurobiol Aging2020; 89: 99–107.
12.
NakamuraAKanekoNVillemagneVL, et al.High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature2018; 554: 249–254.
13.
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.
14.
ThijssenEHJoieRWolfA, et al.Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med2020; 26: 387–397.
15.
RenYLiYTianN, et al.Multimorbidity, cognitive phenotypes, and Alzheimer’s disease plasma biomarkers in older adults: a population-based study. Alzheimers Dement2024; 20: 1550–1561.
16.
Graff-RadfordJ. White matter hyperintensities: relationship to amyloid and tau burden. Brain2019; 142: 2483–2491.
17.
TrieuCHartenACLeeuwisAE, et al.Alzheimer’s disease and cognitive decline in patients with cardiovascular diseases along the heart-brain axis. J Alzheimers Dis2024; 98: 987–1000.
18.
MielkeMMDageJLFrankRD, et al.Performance of plasma phosphorylated tau 181 and 217 in the community. Nat Med2022; 28: 1398–1405.
19.
TwaitELGerritsenLMoonenJEF, et al.Plasma markers of Alzheimer’s disease pathology, neuronal injury, and astrocytic activation and MRI load of vascular pathology and neurodegeneration: the SMART-MR study. J Am Heart Assoc2024; 13: e032134.
20.
SweeneyMDSagareAPZlokovicBV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol2018; 14: 133–150.
21.
EliasSTurkson-OcranRKoiralaB, et al.Heterogeneity in cardiovascular disease risk factors among latino immigrant subgroups: evidence from the 2010 to 2018 national health interview survey. J Am Heart Assoc Cardiovasc Cerebrovasc Dis2023; 12: e027433.
22.
VegaIECabreraLYWygantCM, et al.Alzheimer’s disease in the latino community: intersection of genetics and social determinants of health. J Alzheimers Dis2017; 58: 979–992.
23.
QuesadaOCrousillatDRodriguezF, et al.Cardiovascular disease in hispanic women: JACC review topic of the week. J Am Coll Cardiol2024; 83: 1702–1712.
24.
VardarajanBNFaberKMBirdTD, et al.Age-specific incidence rates for dementia and Alzheimer disease in NIA-LOAD/NCRAD and EFIGA families: national institute on aging genetics initiative for late-onset Alzheimer disease/national cell repository for Alzheimer disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA). JAMA Neurol2014; 71: 315–323.
25.
GuYBeatoJMAmaranteE, et al.Assessment of leisure time physical activity and brain health in a multiethnic cohort of older adults. JAMA Netw Open2020; 3: e2026506.
26.
ZahodneLBSharifianNKraalAZ, et al.Longitudinal associations between racial discrimination and hippocampal and white matter hyperintensity volumes among older black adults. Soc Sci Med2023; 316: 114789.
27.
SternYAndrewsHPittmanJ, et al.Diagnosis of dementia in a heterogeneous population: development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. Arch Neurol1992; 49: 453–460.
28.
BellCC. DSM-IV: diagnostic and statistical manual of mental disorders. JAMA1994; 272: 828–829.
29.
McKhannGMKnopmanDSChertkowH, et al.The diagnosis of dementia due to Alzheimer’s disease: recommendations from the national institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011; 7: 263–269.
30.
ManlyJJBell-McGintySTangM-X, et al.Implementing diagnostic criteria and estimating frequency of mild cognitive impairment in an urban community. Arch Neurol2005; 62: 1739–1746.
31.
AngevaareMJVonkJMJBertolaL, et al.Predictors of incident mild cognitive impairment and its course in a diverse community-based population. Neurology2022; 98: e15–e26.
32.
ReitzCTangM-XSchupfN, et al.A summary risk score for the prediction of Alzheimer disease in elderly persons. Arch Neurol2010; 67: 835–841.
33.
LeeAJSanchezDReyes-DumeyerD, et al.Reliability and validity of self-reported vascular risk factors: hypertension, diabetes, and heart disease, in a multi-ethnic community based study of aging and dementia. J Alzheimers Dis2023; 95: 275–285.
DageJLWennbergAMVAireyDC, et al.Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population-based elderly cohort. Alzheimers Dement2016; 12: 1226–1234.
36.
JanelidzeSMattssonNPalmqvistS. 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.
37.
BosIVosSJBSchindlerSE, et al.Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer’s disease. Alzheimers Dement2019; 15: 1149–1159.
38.
ZlokovicBV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci2011; 12: 723–738.
39.
RoseboroughADSaadLGoodmanM, et al.White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: a meta-analysis, systematic review, and recommendations for future study harmonization. Alzheimers Dement2023; 19: 194–207.
40.
Graff-RadfordJMielkeMMHofrenningEI, et al.Association of plasma biomarkers of amyloid and neurodegeneration with cerebrovascular disease and Alzheimer’s disease. Neurobiol Aging2022; 119: 1–7.
41.
DebetteSMarkusHS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. Lancet Neurol2010; 9: 241–250.
42.
StickelAMcKinnonARuizJ, et al.The impact of cardiovascular risk factors on cognition in Hispanics and non-Hispanic whites. Learn Mem2019; 26: 235–244.
43.
RabinJS. Interactive associations of vascular risk and β-amyloid burden with cognitive decline in clinically normal older individuals: findings from the Harvard aging brain study. JAMA Neurol2019; 76: 1124–1131.
44.
JackCR. NIA-AA Research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement2018; 14: 535–562.
45.
KapasiA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol (Berl)2017; 134: 171–186.
46.
WangYLChenJDuZL, et al.Plasma p-tau181 level predicts neurodegeneration and progression to Alzheimer’s dementia: a longitudinal study. Front Neurol2021; 12: 695696.
47.
ArvanitakisZCapuanoAWLeurgansSE, et al.Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol2016; 15: 934–943.
48.
LivingstonGHuntleyJSommerladA, et al.Dementia prevention, intervention, and care: 2020 report of the Lancet commission. Lancet2020; 396: 413–446.
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