Structural and load-dependent arterial stiffness are differentially associated with cognition or biomarkers of Alzheimer's disease and related dementias: The healthy brain study
Restricted accessResearch articleFirst published online 2026
Structural and load-dependent arterial stiffness are differentially associated with cognition or biomarkers of Alzheimer's disease and related dementias: The healthy brain study
Arterial stiffness is an emerging risk factor for Alzheimer's disease (AD) and related dementias (ADRD) and is assessed by measuring pulse wave velocity (PWV). Recent mathematical modeling has allowed for the delineation of arterial stiffness caused by structural remodeling (S) and blood pressure, termed “load-dependent” stiffening (LD). While we recently demonstrated that S-PWV and LD-PWV are differentially associated with risk for cognitive decline and AD/ADRD brain imaging biomarkers, the associations between paired measures of S-PWV and LD-PWV with cognitive function, AD/ADRD brain imaging biomarkers, and plasma AD biomarkers have not been assessed.
Objective
To conduct a comprehensive analysis combining cross-sectional data from the Wake Forest Alzheimer's Disease Research Center. We hypothesized that higher S-PWV would be associated with worse cognitive function. We also hypothesized that S-PWV and LD-PWV would be differentially associated with brain imaging biomarkers of ADRD and plasma AD biomarkers.
Methods
Multivariable linear regression models were used to relate S-PWV and LD-PWV to all outcomes.
Results
As hypothesized, higher S-PWV, but not LD-PWV, was associated with lower global cognitive function. Higher S-PWV and LD-PWV were differentially associated with AD/ADRD brain MRI biomarkers. We did not observe any significant associations with plasma or PET AD biomarkers in this cohort.
Conclusions
S-PWV was associated with lower cognition, while S-PWV and LD-PWV were differentially associated with brain MRI biomarkers. Interventions specifically targeting arterial stiffness may preserve cognition and brain health in AD/ADRD.
KapasiADeCarliCSchneiderJA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol2017; 134: 171–186.
2.
SchneiderJAArvanitakisZBangW, et al.Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology2007; 69: 2197–2204.
3.
MehtaRISchneiderJA. What is ‘Alzheimer’s disease’? The neuropathological heterogeneity of clinically defined Alzheimer’s dementia. Curr Opin Neurol2021; 34: 237–245.
4.
BoylePAWangTYuL, et al.To what degree is late life cognitive decline driven by age-related neuropathologies?Brain2021; 144: 2166–2175.
5.
FilshteinTJDuggerBNJinL-W, et al.Neuropathological diagnoses of demented hispanic, black, and non-hispanic white decedents seen at an Alzheimer’s disease center. J Alzheimers Dis2019; 68: 145–158.
6.
HanonOHaulonSLenoirH, et al.Relationship between arterial stiffness and cognitive function in elderly subjects with complaints of memory loss. Stroke2005; 36: 2193–2197.
7.
PoelsMMFVan Oijen MariekeMattace-RasoFUS, et al.Arterial stiffness, cognitive decline, and risk of dementia: the Rotterdam study. Stroke2007; 38: 888–892.
8.
HughesTMKullerLHBarinas-mitchellEJM, et al.Arterial stiffness and β-amyloid progression in nondemented elderly adults. JAMA Neurol2014; 71: 562–568.
9.
VasanRSPanSXanthakisV, et al.Arterial stiffness and long-term risk of health outcomes: the framingham heart study. Hypertension2022; 79: 1045–1056.
10.
van SlotenTTProtogerouADHenryRM, et al.Association between arterial stiffness, cerebral small vessel disease and cognitive impairment: a systematic review and meta-analysis. Neurosci Biobehav Rev2015; 53: 121–130.
11.
KimHWHongJJeonJC. Cerebral small vessel disease and Alzheimer’s disease: a review. Front Neurol2020; 11: 927.
12.
PaseMPBeiserAHimaliJJ, et al.Aortic stiffness and the risk of incident mild cognitive impairment and dementia. Stroke2016; 47: 2256–2261.
13.
WangZChenQChenJ, et al.Risk factors of cerebral small vessel disease: a systematic review and meta-analysis. Medicine (Baltimore)2021; 100: e28229.
14.
HughesTMKullerLHBarinas-MitchellEJM, et al.Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults. Neurology2013; 81: 1711–1718.
15.
HughesTMWagenknechtLECraftS, et al.Arterial stiffness and dementia pathology. Neurology2018; 90: e1248–e1256.
16.
CoffinCSuerkenCKBatemanJR, et al.Vascular and microstructural markers of cognitive pathology. Alzheimers Dement (Amst)2022; 14: e12332.
17.
Alvarez-BuenoCCunhaPGMartinez-VizcainoV, et al.Arterial stiffness and cognition among adults: a systematic review and meta-analysis of observational and longitudinal studies. J Am Heart Assoc2020; 9: e014621.
18.
PaltaPSharrettARWeiJ, et al.Central arterial stiffness is associated with structural brain damage and poorer cognitive performance: the ARIC study. J Am Heart Assoc2019; 8: e011045.
19.
RouchLCestacPSallerinB, et al.Pulse wave velocity is associated with greater risk of dementia in mild cognitive impairment patients. Hypertension2018; 72: 1109–1116.
PewowarukRJTedlaYKorcarzCE, et al.Carotid artery stiffening with aging: structural versus load-dependent mechanisms in MESA (the multi-ethnic study of atherosclerosis). Hypertension2022; 79: 150–158.
22.
PewowarukRKorcarzCDe BoerI, et al.Carotid artery stiffness mechanisms are associated with end organ damage and all-cause mortality: MESA (multi-ethnic study of atherosclerosis). J Am Heart Assoc2023; 12: e027517.
23.
PewowarukRJKorcarzCTedlaY, et al.Carotid artery stiffness mechanisms associated with cardiovascular disease events and incident hypertension: the multi-ethnic study of atherosclerosis (MESA). Hypertension2022; 79: 659–666.
24.
PewowarukRKorcarzCTedlaY, et al.Carotid artery stiffness mechanisms in hypertension and their association with echolucency and texture features: the multi-ethnic study of atherosclerosis (MESA). Ultrasound Med Biol2022; 48: 2249–2257.
25.
ArmstrongMKJainSNuckolsV, et al.The association of structural versus load-dependent large artery stiffness mechanisms with cerebrovascular damage and cortical atrophy in humans. Geroscience2024; 46: 5587–5597.
26.
ChirinosJASegersPHughesT, et al.Large-artery stiffness in health and disease. J Am Coll Cardiol2019; 74: 1237–1263.
27.
WilliamsJRDeConneTMPewowarukR, et al.Total and structural carotid artery stiffness are associated with cognitive decline and structural brain abnormalities related to Alzheimer disease and Alzheimer disease-related dementias pathology: the multi-ethnic study of atherosclerosis. J Am Heart Assoc2025; 14: e039925.
28.
MooreEELiuDLiJ, et al.Association of aortic stiffness with biomarkers of neuroinflammation, synaptic dysfunction, and neurodegeneration. Neurology2021; 97: e329–e340.
29.
CooperLLO’DonnellABeiserAS, et al.Association of aortic stiffness and pressure pulsatility with global amyloid-β and regional tau burden among Framingham Heart study participants without dementia. JAMA Neurol2022; 79: 710–719.
30.
PashaEPRutjesETomotoT, et al.Carotid stiffness is associated with brain amyloid-β burden in amnestic mild cognitive impairment. J Alzheimers Dis2020; 74: 925–935.
31.
WheltonPKCareyRMAronowWS, et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension2018; 71: e13–e115.
32.
LaurentSBoutouyrieP. Arterial stiffness: a new surrogate end point for cardiovascular disease?J Nephrol2007; 20: S45–S50.
33.
Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J2010; 31: 2338–2350.
34.
ZhangHSchneiderTWheeler-KingshottCA, et al.NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. NeuroImage2012; 61: 1000–1016.
35.
JungYWongECLiuTT. Multiphase pseudocontinuous arterial spin labeling (MP-PCASL) for robust quantification of cerebral blood flow. Magn Reson Med2010; 64: 799–810.
36.
DaducciACanales-RodríguezEJZhangH, et al.Accelerated microstructure imaging via convex optimization (AMICO) from diffusion MRI data. NeuroImage2015; 105: 32–44.
37.
OishiKFariaAJiangH, et al.Atlas-based whole brain white matter analysis using large deformation diffeomorphic metric mapping: application to normal elderly and Alzheimer’s disease participants. Neuroimage2009; 46: 486–499.
38.
AsllaniIBorogovacABrownTR. Regression algorithm correcting for partial volume effects in arterial spin labeling MRI. Magn Reson Med2008; 60: 1362–1371.
BuxtonRBFrankLRWongEC, et al.A general kinetic model for quantitative perfusion imaging with arterial spin labeling. Magn Reson Med1998; 40: 383–396.
41.
JackCRWisteHJTherneauTM, et al.Associations of amyloid, tau, and neurodegeneration biomarker profiles with rates of memory decline among individuals without dementia. JAMA2019; 321: 2316–2325.
42.
SchmidtPGaserCArsicM, et al.An automated tool for detection of FLAIR-hyperintense white-matter lesions in multiple sclerosis. Neuroimage2012; 59: 3774–3783.
43.
MutsaertsHJPetrJVáclavůL, et al.The spatial coefficient of variation in arterial spin labeling cerebral blood flow images. J Cereb Blood Flow Metab2017; 37: 3184–3192.
44.
RollsETHuangC-CLinC-P, et al.Automated anatomical labelling atlas 3. Neuroimage2020; 206: 116189.
45.
SachsBCSteenlandKZhaoL, et al.Expanded demographic norms for version 3 of the Alzheimer disease Centers’ neuropsychological test battery in the uniform data set. Alzheimer Dis Assoc Disord2020; 34: 191–197.
46.
WeintraubSBesserLDodgeHH, et al.Version 3 of the Alzheimer disease Centers’ neuropsychological test battery in the uniform data set (UDS). Alzheimer Dis Assoc Disord2018; 32: 10–17.
47.
PappKVRentzDMOrlovskyI, et al.Optimizing the preclinical Alzheimer’s cognitive composite with semantic processing: the PACC5. Alzheimers Dement (N Y)2017; 3: 668–677.
48.
QuillenDHughesTMCraftS, et al.Levels of soluble interleukin 6 receptor and Asp358Ala are associated with cognitive performance and Alzheimer disease biomarkers. Neurol Neuroimmunol Neuroinflamm2023; 10: e200095.
49.
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.
50.
AlbertMSDeKoskySTDicksonD, et al.The diagnosis of mild cognitive impairment 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: 270–279.
51.
KlunkWEEnglerHNordbergA, et al.Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann Neurol2004; 55: 306–319.
52.
LockhartSNSchaichCLCraftS, et al.Associations among vascular risk factors, neuroimaging biomarkers, and cognition: preliminary analyses from the multi-ethnic study of atherosclerosis (MESA). Alzheimers Dement2022; 18: 551–560.
53.
RudolphMDSutphenCLRegisterTC, et al.Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer’s disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort. Alzheimers Dement2024; 20: 4159–4173.
54.
VilleneuveSRabinoviciGDCohn-SheehyBI, et al.Existing Pittsburgh compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation. Brain2015; 138: 2020–2033.
55.
LockhartSNSchöllMBakerSL, et al.Amyloid and tau PET demonstrate region-specific associations in normal older people. Neuroimage2017; 150: 191–199.
56.
OssenkoppeleRSchonhautDRSchöllM, et al.Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain2016; 139: 1551–1567.
57.
JackCRBennettDABlennowK, et al.A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology2016; 87: 539–547.
58.
LeuzyAPascoalTAStrandbergO, et al.A multicenter comparison of [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis. Eur J Nucl Med Mol Imaging2021; 48: 2295–2305.
59.
JackCRWisteHJWeigandSD, et al.Defining imaging biomarker cut-points for brain aging and Alzheimer’s disease. Alzheimers Dement2017; 13: 205–216.
60.
RudolphMDSutphenCLRegisterTC, et al.Evaluation of plasma p-tau217 for detecting amyloid pathology in a heterogeneous community-based cohort. Alzheimers Dement2025; 21: e70426.
61.
Pérez-GrijalbaVRomeroJPesiniP, et al.Plasma Aβ42/40 ratio detects early stages of Alzheimer’s disease and correlates with CSF and neuroimaging biomarkers in the AB255 study. J Prev Alzheimers Dis2019; 6: 34–41.
62.
FandosNPérez-GrijalbaVPesiniP, et al.Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimers Dement (Amst)2017; 8: 179–187.
63.
YuXPrzybelskiSAReidRI, et al.NODDI In gray matter is a sensitive marker of aging and early AD changes. Alzheimers Dement (Amst)2024; 16: e12627.
64.
DumontMRoyMJodoinP-M, et al.Free water in white matter differentiates MCI and AD from control subjects. Front Aging Neurosci2019; 11: 270.
65.
KochunovPGlahnDCLancasterJ, et al.Fractional anisotropy of cerebral white matter and thickness of cortical gray matter across the lifespan. Neuroimage2011; 58: 41–49.
66.
GyanwaliBMutsaertsHJTanCS, et al.Association of arterial spin labeling parameters with cognitive decline, vascular events, and mortality in a memory-clinic sample. Am J Geriatr Psychiatry2022; 30: 1298–1309.
67.
GyanwaliBTanCSPetrJ, et al.Arterial spin-labeling parameters and their associations with risk factors, cerebral small-vessel disease, and etiologic subtypes of cognitive impairment and dementia. AJNR Am J Neuroradiol2022; 43: 1418–1423.
68.
MorganCAMelzerTRRobertsRP, et al.Spatial variation of perfusion MRI reflects cognitive decline in mild cognitive impairment and early dementia. Sci Rep2021; 11: 23325.
69.
EmraniSTanleyJSchaichCL, et al.Carotid and regional arterial stiffness and dementia-related imaging biomarkers in the multi-ethnic study of atherosclerosis (MESA). Alzheimers Dement2025; 21: e70688.
70.
MoonSWByunMSYiD, et al.The ankle–brachial Index is associated with cerebral β-amyloid deposition in cognitively normal older adults. J Gerontol A Biol Sci Med Sci2019; 74: 1141–1148.
71.
KimHKulshreshthaAAlonsoA, et al.The association between pulse wave velocity and cerebrospinal fluid biomarkers for Alzheimer’s disease. J Alzheimers Dis2025; 105: 729–735.
