Current evidence has linked peripheral biomarkers of vascular endothelial dysfunction (ED) with cognitive impairment in older adults.
Objective
To investigate the associations of vascular ED with cognitive function while considering the potential influence of lifelong cognitive reserve (CR).
Methods
This population-based cross-sectional study included 1540 dementia-free participants who were aged ≥60 years and living in a rural area of China. Cognitive function was assessed using a neuropsychological test battery. A composite CR score was calculated by integrating education, occupational complexity, mental activity, and social support using a structural equation model. A composite ED score was calculated by averaging the z-scores of serum intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1). Data were analyzed using multiple general linear regression models.
Results
After controlling for multiple potential confounders, higher serum ICAM-1 levels and the composite ED score were significantly associated with lower z-scores in global cognition, verbal fluency, attention, and executive function (p < 0.05), but not with episodic memory z-score (p > 0.05). Higher serum VCAM-1 levels were significantly related with lower z-scores in global cognition, attention, and executive function (p < 0.05), but not with episodic memory or verbal fluency z-score (p > 0.05). There were no statistically significant interactions between ED biomarkers and lifelong CR on cognitive outcomes.
Conclusions
Vascular ED is associated with worse cognitive performance in dementia-free older adults, independent of lifelong CR.
JiaLDuYChuL, et al.Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health2020; 5: e661–e671.
2.
QiuCFratiglioniL. A major role for cardiovascular burden in age-related cognitive decline. Nat Rev Cardiol2015; 12: 267–277.
3.
WalkerKAHoogeveenRCFolsomAR, et al.Midlife systemic inflammatory markers are associated with late-life brain volume: the ARIC study. Neurology2017; 89: 2262–2270.
4.
QiuCKivipeltoMvon StraussE. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci2009; 11: 111–128.
5.
JanssenEKohlerSGeraetsAFJ, et al.Low-grade inflammation and endothelial dysfunction predict four-year risk and course of depressive symptoms: the Maastricht study. Brain Behav Immun2021; 97: 61–67.
6.
HuangYZhangWLinL, et al.Is endothelial dysfunction of cerebral small vessel responsible for white matter lesions after chronic cerebral hypoperfusion in rats?J Neurol Sci2010; 299: 72–80.
7.
LowAMakERoweJB, et al.Inflammation and cerebral small vessel disease: a systematic review. Ageing Res Rev2019; 53: 100916.
8.
RouhlRPDamoiseauxJGLodderJ, et al.Vascular inflammation in cerebral small vessel disease. Neurobiol Aging2012; 33: 1800–1806.
9.
UiterwijkRHuijtsMStaalsJ, et al.Endothelial activation is associated with cognitive performance in patients with hypertension. Am J Hypertens2016; 29: 464–469.
10.
SternY. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol2012; 11: 1006–1012.
11.
LiXSongRQiX, et al.Influence of cognitive reserve on cognitive trajectories: role of brain pathologies. Neurology2021; 97: e1695–e1706.
12.
LavrencicLMRichardsonCHarrisonSL, et al.Is there a link between cognitive reserve and cognitive function in the oldest-old?J Gerontol A Biol Sci Med Sci2018; 73: 499–505.
13.
LiYWangMCongL, et al.Lifelong cognitive reserve, imaging markers of brain aging, and cognitive function in dementia-free rural older adults: a population-based study. J Alzheimers Dis2023; 92: 261–272.
14.
SoldanAPettigrewCZhuY, et al.Cognitive reserve and midlife vascular risk: cognitive and clinical outcomes. Ann Clin Transl Neurol2020; 7: 1307–1317.
15.
TraishAMAbu-ZahraHGuayAT. The brain, the penis and steroid hormones: clinical correlates with endothelial dysfunction. Curr Pharm Des2008; 14: 3723–3736.
16.
MillerVMMulvaghSL. Sex steroids and endothelial function: translating basic science to clinical practice. Trends Pharmacol Sci2007; 28: 263–270.
17.
JiaLQuanMFuY, et al.Dementia in China: epidemiology, clinical management, and research advances. Lancet Neurol2020; 19: 81–92.
18.
LiYDekhtyarSGrandeG, et al.Association of cognitive reserve with transitions across cognitive states and death in older adults: a 15-year follow-up study. Alzheimers Dement2024; 20: 4737–4746.
19.
LiYRenYCongL, et al.Association of lifelong cognitive reserve with dementia and mild cognitive impairment among older adults with limited formal education: a population-based cohort study. Dement Geriatr Cogn Disord2023; 52: 258–266.
20.
WangYDuYLiJ, et al.Lifespan intellectual factors, genetic susceptibility, and cognitive phenotypes in aging: implications for interventions. Front Aging Neurosci2019; 11: 129.
21.
CongLRenYHouT, et al.Use of cardiovascular drugs for primary and secondary prevention of cardiovascular disease among rural-dwelling older Chinese adults. Front Pharmacol2020; 11: 608136.
22.
HanXJiangZLiY, et al.Sex disparities in cardiovascular health metrics among rural-dwelling older adults in China: a population-based study. BMC Geriatr2021; 21: 158.
23.
KivipeltoMMangialascheFSnyderHM, et al.World-Wide FINGERS network: a global approach to risk reduction and prevention of dementia. Alzheimers Dement2020; 16: 1078–1094.
24.
WangYHanXZhangX, et al.Health status and risk profiles for brain aging of rural-dwelling older adults: data from the interdisciplinary baseline assessments in MIND-China. Alzheimers Dement (N Y)2022; 8: e12254.
25.
HusainSAndrewsNPMulcahyD, et al.Aspirin improves endothelial dysfunction in atherosclerosis. Circulation1998; 97: 716–720.
26.
HermidaNBalligandJL. Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: the role of statins. Antioxid Redox Signal2014; 20: 1216–1237.
27.
ShangXZhuZZhangX, et al.Association of a wide range of chronic diseases and apolipoprotein E4 genotype with subsequent risk of dementia in community-dwelling adults: a retrospective cohort study. EClinicalMedicine2022; 45: 101335.
28.
CurrieGDellesC. Vascular biomedicine in an era of chronic disease and multimorbidity. Clin Sci (Lond)2019; 133: 1137–1143.
29.
RenYLiYTianN, et al.Multimorbidity, cognitive phenotypes, and Alzheimer's disease plasma biomarkers in older adults: a population-based study. Alzheimers Dement2024; 20: 1550–1561.
30.
CongLRenYWangY, et al.Mild cognitive impairment among rural-dwelling older adults in China: a community-based study. Alzheimers Dement2023; 19: 56–66.
31.
HanXLiYWangJ, et al.Associations between lifelong cognitive reserve, Alzheimer's disease-related plasma biomarkers, and cognitive function in dementia-free older adults: a population-based study. J Alzheimers Dis2025; 103: 821–832.
32.
ShenZDingSShiS, et al.Association between social support and medication literacy in older adults with hypertension. Front Public Health2022; 10: 987526.
33.
FaWLiangXLiuK, et al.Associations of blood absolute neutrophil count and cytokines with cognitive function in dementia-free participants: a population-based cohort study. J Gerontol A Biol Sci Med Sci2024; 79: glad231.
34.
FassbenderKMossnerRMotschL, et al.Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke1995; 26: 1361–1364.
35.
ChmielewskiPPBoryslawskiKChmielowiecK, et al.The association between total leukocyte count and longevity: evidence from longitudinal and cross-sectional data. Ann Anat2016; 204: 1–10.
36.
HouTLiuKFaW, et al.Association of polygenic risk scores with Alzheimer's disease and plasma biomarkers among Chinese older adults: a community-based study. Alzheimers Dement2024; 20: 6669–6681.
37.
GregoryMAManuel-ApolinarLSanchez-GarciaS, et al.Soluble intercellular adhesion molecule-1 (sICAM-1) as a biomarker of vascular cognitive impairment in older adults. Dement Geriatr Cogn Disord2019; 47: 243–253.
38.
HeringaSMvan den BergEReijmerYD, et al.Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population - the Hoorn study. Psychoneuroendocrinology2014; 40: 108–118.
39.
TchallaAEWelleniusGASorondFA, et al.Elevated soluble vascular cell adhesion molecule-1 is associated with cerebrovascular resistance and cognitive function. J Gerontol A Biol Sci Med Sci2017; 72: 560–566.
40.
LiQYangYReisC, et al.Cerebral small vessel disease. Cell Transplant2018; 27: 1711–1722.
41.
Zanon ZotinMCSveikataLViswanathanA, et al.Cerebral small vessel disease and vascular cognitive impairment: from diagnosis to management. Curr Opin Neurol2021; 34: 246–257.
42.
YousefHCzupallaCJLeeD, et al.Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med2019; 25: 988–1000.
43.
BhatSAGoelRShuklaR, et al.Platelet CD40L induces activation of astrocytes and microglia in hypertension. Brain Behav Immun2017; 59: 173–189.
44.
MadoreCYinZLeibowitzJ, et al.Microglia, lifestyle stress, and neurodegeneration. Immunity2020; 52: 222–240.
45.
Podlesny-DrabiniokAMarcoraEGoateAM. Microglial phagocytosis: a disease-associated process emerging from Alzheimer's disease genetics. Trends Neurosci2020; 43: 965–979.
46.
RawjiKSMishraMKMichaelsNJ, et al.Immunosenescence of microglia and macrophages: impact on the ageing central nervous system. Brain2016; 139: 653–661.
47.
QiuC. Preventing Alzheimer's disease by targeting vascular risk factors: hope and gap. J Alzheimers Dis2012; 32: 721–731.
48.
YangWWangJGuoJ, et al.Association of cognitive reserve indicator with cognitive decline and structural brain differences in middle and older age: findings from the UK Biobank. J Prev Alzheimers Dis2024; 11: 739–748.
49.
DurraniRFriedrichMGSchulzeKM, et al.Effect of cognitive reserve on the association of vascular brain injury with cognition: analysis of the PURE and CAHHM studies. Neurology2021; 97: e1707–e1716.
50.
MortamaisMPortetFBrickmanAM, et al.Education modulates the impact of white matter lesions on the risk of mild cognitive impairment and dementia. Am J Geriatr Psychiatry2014; 22: 1336–1345.
51.
MoreauKLHildrethKLMeditzAL, et al.Endothelial function is impaired across the stages of the menopause transition in healthy women. J Clin Endocrinol Metab2012; 97: 4692–4700.
52.
HaywardCSKellyRP. Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol1997; 30: 1863–1871.
53.
BurtVLWheltonPRoccellaEJ, et al.Prevalence of hypertension in the US adult population. Results from the third national health and nutrition examination survey, 1988–1991. Hypertension1995; 25: 305–313.
54.
IadecolaC. The pathobiology of vascular dementia. Neuron2013; 80: 844–866.
55.
BeranMJansenWJOomensJE, et al.Biomarkers of endothelial dysfunction and cognition: a two-step IPD meta-analysis. Alzheimers Dement2024; 20: 8402–8411.
56.
LiborioABde MedeirosCSantosLL, et al.Endothelium-related biomarkers and cognitive decline in prevalent hemodialysis patients: a prospective cohort study. Eur J Neurol2024; 31: e16438.
