The prevalence of Alzheimer's disease (AD) is on the rise due to the global aging population. AD is the most common cause of dementia, accounting for 60–80% of all cases, which makes it a significant health concern. In recent years, the failure to develop targeted pathological drugs has led researchers to shift their focus. The blood-brain barrier (BBB) is a specialized structure that separates the circulating blood from the brain tissue and tightly regulates the passage of molecules, ions, and cells between the blood and the brain. Through a comprehensive review of current literature, we highlight the multifaceted role of BBB dysfunction in the pathogenesis of AD and discuss the complex mechanisms involved. Changes in the structure and function of endothelial cells, pericytes, and astrocytes, along with elevated expression of the highest-risk gene APOE4, can all lead to BBB damage, thereby promoting the onset of AD. Furthermore, we explore potential therapeutic targets to preserve BBB integrity and function to mitigate AD progression. This review underscores the significance of ongoing research efforts in elucidating the intricate interplay between BBB integrity and AD pathology, offering valuable insights for future investigations and therapeutic strategies.
NehraGBauerBHartzAMS. Blood-brain barrier leakage in Alzheimer's disease: from discovery to clinical relevance. Pharmacol Ther2022; 234: 108119.
2.
PerneczkyRDomGChanA, et al.Anti-amyloid antibody treatments for Alzheimer's disease. Eur J Neurol2024; 31: e16049.
3.
HuangYYGanYHYangL, et al.Depression in Alzheimer's disease: epidemiology, mechanisms, and treatment. Biol Psychiatry2024; 95: 992–1005.
4.
ZhangJZhangYWangJ, et al.Recent advances in Alzheimer's disease: mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther2024; 9: 211.
5.
BleibelMEl CheikhASadierNS, et al.The effect of music therapy on cognitive functions in patients with Alzheimer's disease: a systematic review of randomized controlled trials. Alzheimers Res Ther2023; 15: 65.
6.
ZhangYChenHLiR, et al.Amyloid β-based therapy for Alzheimer's disease: challenges, successes and future. Signal Transduct Target Ther2023; 8: 248.
7.
BeshirSAAadithsooryaAMParveenA, et al.Aducanumab therapy to treat Alzheimer's disease: a narrative review. Int J Alzheimers Dis2022; 2022: 9343514.
8.
RowleyPASamsonovAABetthauserTJ, et al.Amyloid and tau PET imaging of Alzheimer disease and other neurodegenerative conditions. Semin Ultrasound CT MR2020; 41: 572–583.
9.
ZenaroEPiacentinoGConstantinG. The blood-brain barrier in Alzheimer's disease. Neurobiol Dis2017; 107: 41–56.
10.
ZhaoMJiangX-FZhangH-Q, et al.Interactions between glial cells and the blood-brain barrier and their role in Alzheimer's disease. Ageing Res Rev2021; 72: 101483.
11.
LengFEdisonP. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?Nat Rev Neurol2021; 17: 157–172.
12.
JianMKwanJSBuntingM, et al.Adiponectin suppresses amyloid-β oligomer (AβO)-induced inflammatory response of microglia via AdipoR1-AMPK-NF-κB signaling pathway. J Neuroinflammation2019; 16: 110.
13.
IsingCVenegasCZhangS, et al.NLRP3 Inflammasome activation drives tau pathology. Nature2019; 575: 669–673.
14.
FuWYWangXIpNY. Targeting neuroinflammation as a therapeutic strategy for Alzheimer's disease: mechanisms, drug candidates, and new opportunities. ACS Chem Neurosci2019; 10: 872–879.
BussianTJAzizAMeyerCF, et al.Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature2018; 562: 578–582.
17.
SumsuzzmanDMUddinMSKabirMT, et al.Microglia in Alzheimer's disease: a favorable cellular target to ameliorate Alzheimer's pathogenesis. Mediators Inflamm2022; 2022: 6052932.
18.
HamelinLLagardeJDorothéeG, et al.Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain2016; 139: 1252–1264.
19.
QiuWQWalshDMYeZ, et al.Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem1998; 273: 32730–32738.
20.
FrautschySAYangFIrrizarryM, et al.Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol1998; 152: 307–317.
21.
JimenezSBaglietto-VargasDCaballeroC, et al.Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci2008; 28: 11650–11661.
22.
Serrano-PozoADasSHymanBT. APOE And Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol2021; 20: 68–80.
23.
TeraoIKodamaW. Comparative efficacy, tolerability and acceptability of donanemab, lecanemab, aducanumab and lithium on cognitive function in mild cognitive impairment and Alzheimer's disease: a systematic review and network meta-analysis. Ageing Res Rev2024; 94: 102203.
24.
Høilund-CarlsenPFAlaviABarrioJR, et al.Donanemab, another anti-Alzheimer's drug with risk and uncertain benefit. Ageing Res Rev2024; 99: 102348.
25.
Van DyckCHSwansonCJAisenP, et al.Lecanemab in early Alzheimer's disease. N Engl J Med2023; 388: 9–21.
26.
MarascoRA. Current and evolving treatment strategies for the Alzheimer disease continuum. Am J Manag Care2020; 26: S167–S176.
27.
Kumar NelsonVJhaNKNuliMV, et al.Unveiling the impact of aging on BBB and Alzheimer's disease: factors and therapeutic implications. Ageing Res Rev2024; 98: 102224.
28.
ShimizuFNakamoriM. Blood-brain barrier disruption in neuroimmunological disease. Int J Mol Sci2024; 25: 10625.
29.
ChenTDaiYHuC, et al.Cellular and molecular mechanisms of the blood-brain barrier dysfunction in neurodegenerative diseases. Fluids Barriers CNS2024; 21: 60.
30.
DanemanRPratA. The blood–brain barrier. Cold Spring Harb Perspect Biol2015; 7: a020412.
31.
CorreiaACMonteiroARSilvaR, et al.Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: crossing or circumventing the blood-brain barrier (BBB) to manage neurological disorders. Adv Drug Deliv Rev2022; 189: 114485.
32.
HeQLiuHHuangC, et al.Herpes simplex virus 1-induced blood-brain barrier damage involves apoptosis associated with GM130-mediated Golgi stress. Front Mol Neurosci2020; 13: 2.
33.
LiuYJohnstonCJarousseN, et al.Association between herpes simplex virus type 1 and the risk of Alzheimer’s disease: a retrospective case–control study. BMJ Open2025; 15: e093946.
34.
EimerWAVijaya KumarDKNavalpur ShanmugamNK, et al.Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron2018; 99: 56–63.e3.
35.
Simöes Da GamaCMorin-BrureauM. Study of BBB dysregulation in neuropathogenicity using integrative human model of blood-brain barrier. Front Cell Neurosci2022; 16: 863836.
36.
PengBHaoSTongZ, et al.Blood-brain barrier (BBB)-on-a-chip: a promising breakthrough in brain disease research. Lab Chip2022; 22: 3579–3602.
37.
KurzCWalkerLRauchmannBS, et al.Dysfunction of the blood-brain barrier in Alzheimer's disease: evidence from human studies. Neuropathol Appl Neurobiol2022; 48: e12782.
38.
DeekenJFLöscherW. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res2007; 13: 1663–1674.
39.
DenesAHansenCEOezorhanU, et al.Endothelial cells and macrophages as allies in the healthy and diseased brain. Acta Neuropathol2024; 147: 38.
40.
SchurhoffNToborekM. Circadian rhythms in the blood-brain barrier: impact on neurological disorders and stress responses. Mol Brain2023; 16: 5.
41.
MaiuoloJGliozziMMusolinoV, et al.The “Frail” brain blood barrier in neurodegenerative diseases: role of early disruption of Endothelial cell-to-cell connections. Int J Mol Sci2018; 19: 2693.
42.
ProfaciCPMunjiRNPulidoRS, et al.The blood-brain barrier in health and disease: important unanswered questions. J Exp Med2020; 217: e20190062.
43.
KadryHNooraniBCuculloL. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS2020; 17: 69.
ArmulikAGenovéGBetsholtzC. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell2011; 21: 193–215.
46.
AttwellDMishraAHallCN, et al.What is a pericyte?J Cereb Blood Flow Metab2016; 36: 451–455.
47.
ArmulikAGenovéGMäeM, et al.Pericytes regulate the blood-brain barrier. Nature2010; 468: 557–561.
48.
WinklerEABellRDZlokovicBV. Central nervous system pericytes in health and disease. Nat Neurosci2011; 14: 1398–1405.
49.
DanemanRZhouLKebedeAA, et al.Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature2010; 468: 562–566.
50.
HeSHouTZhouJ, et al.Endothelial cells promote migration of mesenchymal stem cells via PDGF-BB/PDGFRβ-Src-Akt in the context of inflammatory microenvironment upon bone defect. Stem Cells Int2022; 2022: 2401693.
51.
OkekawaAWadaTOnogiY, et al.Platelet-derived growth factor signaling in pericytes promotes hypothalamic inflammation and obesity. Mol Med2024; 30: 21.
52.
SmythLCDHighetBJanssonD, et al.Characterisation of PDGF-BB:PDGFRβ signalling pathways in human brain pericytes: evidence of disruption in Alzheimer's disease. Commun Biol2022; 5: 235.
53.
SimardMArcuinoGTakanoT, et al.Signaling at the gliovascular interface. J Neurosci2003; 23: 9254–9262.
54.
IadecolaC. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron2017; 96: 17–42.
55.
HuangLNakamuraYLoEH, et al.Astrocyte signaling in the neurovascular unit after central nervous system injury. Int J Mol Sci2019; 20: 282.
56.
LovickTABrownLAKeyBJ. Neuronal activity-related coupling in cortical arterioles: involvement of astrocyte-derived factors. Exp Physiol2005; 90: 131–140.
57.
SofroniewMVVintersHV. Astrocytes: biology and pathology. Acta Neuropathol2010; 119: 7–35.
58.
PivoriūnasAVerkhratskyA. Astrocyte–endotheliocyte axis in the regulation of the blood–brain barrier. Neurochem Res2021; 46: 2538–2550.
59.
LiuDLiaoPLiH, et al.Regulation of blood-brain barrier integrity by Dmp1-expressing astrocytes through mitochondrial transfer. Sci Adv2024; 10: eadk2913.
60.
AbramovAYCanevariLDuchenMR. β-Amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci2004; 24: 565–575.
61.
HenekaMTRodríguezJJVerkhratskyA. Neuroglia in neurodegeneration. Brain Res Rev2010; 63: 189–211.
62.
ThomsenMSRoutheLJMoosT. The vascular basement membrane in the healthy and pathological brain. J Cereb Blood Flow Metab2017; 37: 3300–3317.
63.
FranzeK. The mechanical control of nervous system development. Development2013; 140: 3069–3077.
64.
LepelletierFXMannDMRobinsonAC, et al.Early changes in extracellular matrix in Alzheimer's disease. Neuropathol Appl Neurobiol2017; 43: 167–182.
65.
HeldFMorrisAWJPiriciD, et al.Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease. Clin Sci (Lond)2017; 131: 1001–1013.
66.
ThalDRGhebremedhinERübU, et al.Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol2002; 61: 282–293.
67.
KiuchiYIsobeYFukushimaK. Entactin-induced inhibition of human amyloid beta-protein fibril formation in vitro. Neurosci Lett2001; 305: 119–122.
68.
KiuchiYIsobeYFukushimaK, et al.Disassembly of amyloid beta-protein fibril by basement membrane components. Life Sci2002; 70: 2421–2431.
69.
SweeneyMDZhaoZMontagneA, et al.Blood-brain barrier: from physiology to disease and back. Physiol Rev2019; 99: 21–78.
70.
GeninEHannequinDWallonD, et al.APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry2011; 16: 903–907.
71.
LiuCCLiuCCKanekiyoT, et al.Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol2013; 9: 106–118.
72.
TanziRE. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med2012; 2: a006296.
73.
VerghesePBCastellanoJMHoltzmanDM. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol2011; 10: 241–252.
74.
ZhongNWeisgraberKH. Understanding the association of Apolipoprotein E4 with Alzheimer disease: clues from its structure. J Biol Chem2009; 284: 6027–6031.
75.
BlumenfeldJYipOKimMJ, et al.Cell type-specific roles of APOE4 in Alzheimer disease. Nat Rev Neurosci2024; 25: 91–110.
76.
JacksonRJMeltzerJCNguyenH, et al.APOE4 Derived from astrocytes leads to blood–brain barrier impairment. Brain2022; 145: 3582–3593.
77.
JungESChoiHMook-JungI. Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research. Mol Neurodegener2025; 20: 37.
78.
FossatiSGhisoJRostagnoA. TRAIL Death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer’s Aβ. Cell Death Dis2012; 3: e321.
79.
ZhouXShiQZhangX, et al.ApoE4-mediated blood-brain barrier damage in Alzheimer's disease: progress and prospects. Brain Res Bull2023; 199: 110670.
80.
CaselliRJWalkerDSueL, et al.Amyloid load in nondemented brains correlates with APOE ε4. Neurosci Lett2010; 473: 168–171.
81.
YipAGMcKeeACGreenRC, et al.APOE, vascular pathology, and the AD brain. Neurology2005; 65: 259–265.
82.
Serrano-PozoAQianJMonsellSE, et al.APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann Neurol2015; 77: 917–929.
83.
YiLXZengLWangQ, et al.Reelin links Apolipoprotein E4, tau, and amyloid-β in Alzheimer's disease. Ageing Res Rev2024; 98: 102339.
84.
PoblanoJCastillo-TobíasIBerlangaL, et al.Drugs targeting APOE4 that regulate beta-amyloid aggregation in the brain: therapeutic potential for Alzheimer's disease. Basic Clin Pharmacol Toxicol2024; 135: 237–249.
85.
FoleyKEWilcockDM. Three major effects of APOE(ε4) on Aβ immunotherapy induced ARIA. Front Aging Neurosci2024; 16: 1412006.
86.
LasloALasloLArbănașiEM, et al.Pathways to Alzheimer's disease: the intersecting roles of clusterin and Apolipoprotein E in amyloid-β regulation and neuronal health. Pathophysiology2024; 31: 545–558.
87.
EbrightBDuroMVChenK, et al.Effects of APOE4 on omega-3 brain metabolism across the lifespan. Trends Endocrinol Metab2024; 35: 745–757.
88.
VanceJMFarrerLAHuangY, et al.Report of the APOE4 national institute on aging/Alzheimer disease sequencing project consortium working group: reducing APOE4 in carriers is a therapeutic goal for Alzheimer's disease. Ann Neurol2024; 95: 625–634.
89.
WindhamIACohenS. The cell biology of APOE in the brain. Trends Cell Biol2024; 34: 338–348.
90.
WangZ-HXiaYLiuP, et al.APOE4 Activates C/EBPβ/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer’s disease. Prog Neurobiol2021; 202: 102032.
91.
PohlkampTXianXWongCH, et al.NHE6 Depletion corrects APOE4-mediated synaptic impairments and reduces amyloid plaque load. Elife2021; 10: e72034.
92.
HuangYAZhouBWernigM, et al.APOE2, APOE3, and APOE4 differentially stimulate APP transcription and aβ secretion. Cell2017; 168: 427–441.e21.
93.
TaoQAngTFADeCarliC, et al.Association of chronic low-grade inflammation with risk of Alzheimer disease in APOE4 carriers. JAMA Netw Open2018; 1: e183597.
94.
VitekMPBrownCMColtonCA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging2009; 30: 1350–1360.
95.
LynchJRTangWWangH, et al.APOE Genotype and an APOE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem2003; 278: 48529–48533.
96.
StomrudEBjörkqvistMJanciauskieneS, et al.Alterations of matrix metalloproteinases in the healthy elderly with increased risk of prodromal Alzheimer's disease. Alzheimers Res Ther2010; 2: 20.
97.
OikariLEPanditRStewartR, et al.Altered brain endothelial cell phenotype from a familial Alzheimer mutation and its potential implications for amyloid clearance and drug delivery. Stem Cell Rep2020; 14: 924–939.
98.
Cabral-PachecoGAGarza-VelozICastruita-De la RosaC, et al.The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci2020; 21: 9739.
99.
YangYKimura-OhbaSThompsonJ, et al.Rodent models of vascular cognitive impairment. Transl Stroke Res2016; 7: 407–414.
100.
RempeRGHartzAMSBauerB. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab2016; 36: 1481–1507.
101.
YangYEstradaEYThompsonJF, et al.Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab2007; 27: 697–709.
102.
YuMNieYYangJ, et al.Integrative multi-omic profiling of adult mouse brain endothelial cells and potential implications in Alzheimer’s disease. Cell Rep2023; 42: 113392.
103.
GastfriendBDNishiharaHCanfieldSG, et al.Wnt signaling mediates acquisition of blood-brain barrier properties in naïve endothelium derived from human pluripotent stem cells. Elife2021; 10: e70992.
104.
GulejRCsikBFaakyeJ, et al.Endothelial deficiency of insulin-like growth factor-1 receptor leads to blood–brain barrier disruption and accelerated endothelial senescence in mice, mimicking aspects of the brain aging phenotype. Microcirculation2024; 31: e12840.
105.
LiPFanH. Pericyte loss in diseases. Cells2023; 12: 1931.
106.
ZhangYMuBRRanZ, et al.Pericytes in Alzheimer's disease: key players and therapeutic targets. Exp Neurol2024; 379: 114825.
107.
LiYYGuoDDDuanRN, et al.Interactions between beta-amyloid and pericytes in Alzheimer's disease. Front Biosci (Landmark Ed)2024; 29: 136.
108.
YaoYChenZLNorrisEH, et al.Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun2014; 5: 3413.
109.
HeLVanlandewijckMRaschpergerE, et al.Analysis of the brain mural cell transcriptome. Sci Rep2016; 6: 35108.
110.
De KortAMKuiperijHBKerstenI, et al.Normal cerebrospinal fluid concentrations of PDGFRβ in patients with cerebral amyloid angiopathy and Alzheimer's disease. Alzheimers Dement2022; 18: 1788–1796.
111.
ShiHKoronyoYRentsendorjA, et al.Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina. Acta Neuropathol2020; 139: 813–836.
112.
Fernandez-KlettFBrandtLFernández-ZapataC, et al.Denser brain capillary network with preserved pericytes in Alzheimer's disease. Brain Pathol2020; 30: 1071–1086.
113.
YamazakiYShinoharaMYamazakiA, et al.APOE (Apolipoprotein E) in brain pericytes regulates endothelial function in an isoform-dependent manner by modulating basement membrane components. Arterioscler Thromb Vasc Biol2020; 40: 128–144.
114.
Vazquez-LiebanasENaharKBertuzziG, et al.Adult-induced genetic ablation distinguishes PDGFB roles in blood-brain barrier maintenance and development. J Cereb Blood Flow Metab2022; 42: 264–279.
115.
KimbroughIFRobelSRobersonED, et al.Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain2015; 138: 3716–3733.
116.
HoshiAYamamotoTShimizuK, et al.Characteristics of aquaporin expression surrounding senile plaques and cerebral amyloid angiopathy in Alzheimer disease. J Neuropathol Exp Neurol2012; 71: 750–759.
117.
ZeppenfeldDMSimonMHaswellJD, et al.Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol2017; 74: 91–99.
118.
SharonGSampsonTRGeschwindDH, et al.The central nervous system and the gut microbiome. Cell2016; 167: 915–932.
119.
WangYHuHLiuX, et al.Hypoglycemic medicines in the treatment of Alzheimer's disease: pathophysiological links between AD and glucose metabolism. Front Pharmacol2023; 14: 1138499.
120.
Gonzalez-MarreroIHernandez-AbadLGCastaneyra-RuizL, et al.Changes in the choroid plexuses and brain barriers associated with high blood pressure and ageing. Neurologia (Engl Ed)2022; 37: 371–382.
121.
FengZFangCMaY, et al.Obesity-induced blood-brain barrier dysfunction: phenotypes and mechanisms. J Neuroinflammation2024; 21: 110.
122.
MontagneAZhaoZZlokovicBV. Alzheimer's disease: a matter of blood-brain barrier dysfunction?J Exp Med2017; 214: 3151–3169.
123.
ZlokovicBV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci2011; 12: 723–738.
124.
ZhangWLiPGuoX, et al.Role of moesin, Src, and ROS in advanced glycation end product-induced vascular endothelial dysfunction. Microcirculation2017; 24: e12358.
125.
ShiSMSuhRJShonDJ, et al.Glycocalyx dysregulation impairs blood–brain barrier in ageing and disease. Nature2025; 639: 985–994.
126.
AlkhalifaAEAl-GhraiybahNFOdumJ, et al.Blood–brain barrier breakdown in Alzheimer’s disease: mechanisms and targeted strategies. Int J Mol Sci2023; 24: 16288.
127.
SripetchwandeeJChattipakornNChattipakornSC. Links between obesity-induced brain insulin resistance, brain mitochondrial dysfunction, and dementia. Front Endocrinol (Lausanne)2018; 9: 496.
128.
Candelario-JalilEYangYRosenbergGA. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience2009; 158: 983–994.
129.
CouchaMAbdelsaidMWardR, et al.Impact of metabolic diseases on cerebral circulation: structural and functional consequences. Compr Physiol2018; 8: 773–799.
130.
BiesselsGJDespaF. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol2018; 14: 591–604.
131.
van SlotenTTSedaghatSCarnethonMR, et al.Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. Lancet Diabetes Endocrinol2020; 8: 325–336.
132.
KelleherRJSoizaRL. Evidence of endothelial dysfunction in the development of Alzheimer's disease: is Alzheimer's a vascular disorder?Am J Cardiovasc Dis2013; 3: 197–226.
133.
XieLKangHXuQ, et al.Sleep drives metabolite clearance from the adult brain. Science2013; 342: 373–377.
134.
XuCApostolovaLGOblakAL, et al.Association of hypercholesterolemia with Alzheimer’s disease pathology and cerebral amyloid angiopathy. J Alzheimers Dis2020; 73: 1305–1311.
135.
SaeedAAGenovéGLiT, et al.Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain. J Biol Chem2014; 289: 23712–23722.
136.
DolanHCrainBTroncosoJ, et al.Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging cohort. Ann Neurol2010; 68: 231–240.
137.
InoueYShueFBuG, et al.Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer’s disease. Mol Neurodegener2023; 18: 46.
138.
DuongMTNasrallahIMWolkDA, et al.Cholesterol, atherosclerosis, and APOE in vascular contributions to cognitive impairment and dementia (VCID): potential mechanisms and therapy. Front Aging Neurosci2021; 13: 647990.
139.
MurakamiTFelinskiEAAntonettiDA. Occludin phosphorylation and ubiquitination regulate tight junction trafficking and vascular endothelial growth factor-induced permeability. J Biol Chem2009; 284: 21036–21046.
140.
JohnsonKAFoxNCSperlingRA, et al.Brain imaging in Alzheimer disease. Cold Spring Harb Perspect Med2012; 2: a006213.
141.
WinklerEANishidaYSagareAP, et al.GLUT1 Reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci2015; 18: 521–530.
142.
LiXCoyleDMaguireL, et al.Gray matter concentration and effective connectivity changes in Alzheimer's disease: a longitudinal structural MRI study. Neuroradiology2011; 53: 733–748.
143.
AgostiEZeppieriMAntoniettiS, et al.Navigating the nose-to-brain route: a systematic review on lipid-based nanocarriers for central nervous system disorders. Pharmaceutics2024; 16: 329.
144.
HasanIRoySEhexigeE, et al.A state-of-the-art liposome technology for glioblastoma treatment. Nanoscale2023; 15: 18108–18138.
145.
ZakharovaLGaynanovaGVasilievaE, et al.Recent nanoscale carriers for therapy of Alzheimer's disease: current strategies and perspectives. Curr Med Chem2023; 30: 3743–3774.
146.
ZeynalzadehEKhodadadiEKhodadadiE, et al.Navigating the neurological frontier: macromolecular marvels in overcoming blood-brain barrier challenges for advanced drug delivery. Heliyon2024; 10: e35562.
147.
TeixeiraMILopesCMAmaralMH, et al.Surface-modified lipid nanocarriers for crossing the blood-brain barrier (BBB): a current overview of active targeting in brain diseases. Colloids Surf B Biointerfaces2023; 221: 112999.
148.
Oller-SalviaBSánchez-NavarroMCiudadS, et al.MiniAp-4: a venom-inspired peptidomimetic for brain delivery. Angew Chem Int Ed Engl2016; 55: 572–575.
149.
LamFCMortonSWWyckoffJ, et al.Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles. Nat Commun2018; 9: 1991.
150.
SongJLuCLeszekJ, et al.Design and development of nanomaterial-based drug carriers to overcome the blood-brain barrier by using different transport mechanisms. Int J Mol Sci2021; 22: 10118.
151.
MoreiraRNóbregaCde AlmeidaLP, et al.Brain-targeted drug delivery - nanovesicles directed to specific brain cells by brain-targeting ligands. J Nanobiotechnology2024; 22: 260.
152.
AlhodiebFSRahmanMABarkatMA, et al.Nanomedicine-driven therapeutic interventions of autophagy and stem cells in the management of Alzheimer's disease. Nanomedicine (Lond)2023; 18: 145–168.
153.
KumarPWuHMcBrideJL, et al.Transvascular delivery of small interfering RNA to the central nervous system. Nature2007; 448: 39–43.
154.
GaoYWangZ-YZhangJ, et al.RVG-peptide-linked trimethylated chitosan for delivery of siRNA to the brain. Biomacromolecules2014; 15: 1010–1018.
155.
WangCWangSXueY, et al.Intravenous administration of blood–brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system. Nat Biotechnol. Epub ahead of print 25 Nov 2024. DOI: 10.1038/s41587-024-02487-7
156.
EmerichDFDeanRLOsbornC, et al.The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation. Clin Pharmacokinet2001; 40: 105–123.
157.
JuvenalGMeinerzCAyupeAC, et al.Bradykinin promotes immune responses in differentiated embryonic neurospheres carrying APPswe and PS1dE9 mutations. Cell Biosci2024; 14: 82.
158.
WangQHuangXSuY, et al.Activation of Wnt/β-catenin pathway mitigates blood-brain barrier dysfunction in Alzheimer's disease. Brain2022; 145: 4474–4488.
159.
ZhouXLiJQuanS, et al.Andrographolide improves APOE4-mediated blood–brain barrier injury by alleviating inflammation. Mol Neurobiol2024; 61: 7950–7967.
160.
NayakVPatraSRoutS, et al.Regulation of neuroinflammation in Alzheimer's disease via nanoparticle-loaded phytocompounds with anti-inflammatory and autophagy-inducing properties. Phytomedicine2024; 122: 155150.
161.
BurkeMRSotiropoulosIWaitesCL. The multiple roles of chronic stress and glucocorticoids in Alzheimer's disease pathogenesis. Trends Neurosci2024; 47: 933–948.
162.
SakaiAHanJCatoAC, et al.Glucocorticoids synergize with IL-1beta to induce TLR2 expression via MAP kinase phosphatase-1-dependent dual Inhibition of MAPK JNK and p38 in epithelial cells. BMC Mol Biol2004; 5: 2.
163.
WeberMDFrankMGSobeskyJL, et al.Blocking toll-like receptor 2 and 4 signaling during a stressor prevents stress-induced priming of neuroinflammatory responses to a subsequent immune challenge. Brain Behav Immun2013; 32: 112–121.
164.
BusilloJMAzzamKMCidlowskiJA. Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome. J Biol Chem2011; 286: 38703–38713.
165.
CattaneoAFerrariCTurnerL, et al.Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study. Transl Psychiatry2020; 10: 232.
166.
FrankMGHershmanSAWeberMD, et al.Chronic exposure to exogenous glucocorticoids primes microglia to pro-inflammatory stimuli and induces NLRP3 mRNA in the hippocampus. Psychoneuroendocrinology2014; 40: 191–200.
167.
DingYGaoZGJacobsonKA, et al.Dexamethasone enhances ATP-induced inflammatory responses in endothelial cells. J Pharmacol Exp Ther2010; 335: 693–702.
168.
AllenSJWatsonJJShoemarkDK, et al.GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther2013; 138: 155–175.
169.
NagaharaAHTuszynskiMH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov2011; 10: 209–219.
170.
EdisonPFemminellaGDRitchieC, et al.MRI Changes following treatment of glp-1 analogue, liraglutide in Alzheimer’s disease. Alzheimers Dement2023; 19: e080538.
171.
EdisonPFemminellaGDRitchieCW, et al.Evaluation of liraglutide in the treatment of Alzheimer's disease. Alzheimers Dement2021; 17: e057848.
172.
QiFZuoZHuK, et al.VEGF-A in serum protects against memory impairment in APP/PS1 transgenic mice by blocking neutrophil infiltration. Mol Psychiatry2023; 28: 4374–4389.
173.
ZhangMZhangZLiH, et al.Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer’s disease. Transl Neurodegener2024; 13: 1.
