Table 1:
summary of cited literature regarding metabolic dysfunction at the BBB and AD and the role of BBB dysfunction in AD.
| Metabolic dysfunction at the BBB | Mooradian (1997)21 | Diabetes is associated with pathological changes to BBB microvasculature |
| Rhea et al. (2017)22 | Review: obesity decreases expression of TJ proteins, thins cerebrovasculature, and increases neuroinflammation | |
| Chang et al. (2014)39 | HFD disrupts BBB function and increases neuronal apoptosis | |
| Salameh et al. (2019)40 | DIO disrupts hippocampal and hypothalamic BBB | |
| Roy et al. (2010)43 | Diabetes causes thickening of vascular basement membrane | |
| Sajja et al. (2014)59 | Hypoglycemia reduces claudin-5 and disrupts zona occluden-1 function | |
| Serlin et al. (2011)53 | Diabetes induces vascular damage, impairs glucose transport, and increases RAGE signaling | |
| Yamagishi and Imaizumi (2005)55 | Hyperglycemia increases productions of advanced glycation end products and reactive oxygen species, resulting in vascular | |
| Li et al. (2016)83 | BBB disruption is more severe in obese mice following ischemic stroke | |
| Metabolic dysfunction in AD | Allen et al. (2004)20 | Meta-analysis: T2DM is associated with increased risk and faster progression of AD |
| Roberts et al. (2014)24 | Mid-life diabetes is associated with loss of brain volume and increased cognitive impairment | |
| McNay et al. (2010)25, McNay & Recknagel (2011)26 | Central insulin resistance impairs spatial working memory | |
| Bruel et al. (2011)27 | T2DM is associated with reduction in HPC volume in obese adolescents | |
| den Heijer et al. (2003)28 | T2DM is associated with reduction in HPC volume | |
| Gold et al. (2007)29 | T2DM associated with reduced HPC volume and impaired cognitive performance in middle aged | |
| McNay and Pearson-Leary (2020)33 | Reduced glucose transport associated with cognitive impairment in rats | |
| Biessels & Reagan (2015)36 | IR is evident in brains of patients with T2DM and AD | |
| Talbot et al. (2012)37 | Reduced insulin signaling evident in the HPC in AD patients without T2DM | |
| Hardigan et al. (2016)42 | Diabetes induces cerebrovascular dysfunction resulting in cognitive impairment | |
| Mosconi et al. (2010)66, (2013)65 | Decreased brain glucose utilization occurs early in AD disease progression and correlates with severity | |
| Swaminathan et al. (2018)79 | Peripheral insulin administration alters the clearance of Aβ40 and Aβ42 | |
| Small et al. (1995)98 | APOE4 carriers display reduced parietal metabolism | |
| BBB dysfunction in AD | Rhea et al. (2020)91 | Review of the impact of APOE4 and insulin on the BBB |
| Takechi et al. (2017)38 | Cognitive decline is preceded by BBB dysfunction in IR mice | |
| Horwood and Davies (1994)44, Kalaria and Harik (1989)46, Mooriadian (1997)21, Simpson et al. (1994)47 | BBB glucose transport reduced in AD | |
| Bowman et al. (2018)52 | AD patients with dyslipidemia exhibit increased BBB permeability | |
| Chakraborty et al. (2017)61 | Review: vascular disturbance impairs BBB function and increased AD risk | |
| Yang et al. (2020)62 | Cerebral hypoperfusion increases neuroinflammation, Aβ accumulation, and BBB permeability | |
| Liu et al. (2019)63 | Chronic hypoperfusion reduces BBB integrity and decreases pericyte coverage | |
| Montagne et al. (2015)67 | BBB breakdown is evident in early AD and correlates with degree of cognitive impairment | |
| Montagne et al. (2020)68 | BBB breakdown in APOE4 carriers precedes and predicts cognitive decline independent of Aβ or tau | |
| Nation et al. (2019)69 | BBB breakdown is evident in individuals with early mild cognitive impairment independent of Aβ or tau | |
| Montagne et al. (2021)74, Bell et al. (2012)93, Halliday et al. (2016)94 | APOE4 accelerated BBB dysfunction is dependent on the Cyclophilin A/MMP9 pathway and independent of Aβ | |
| Cortes-Canteli et al. (2010)75 | Fibrinogen clots colocalize with Aβ, and fibrinogen depletion improves cognitive performance | |
| Hultman et al. (2013)76 | APOE4 exacerbates Aβ associated fibrinogen deposition | |
| Miners et al. (2018)77 | Decreased BBB integrity and pericyte marker PDGFRβ is associated with increased fibrinogen deposition and Aβ accumulation in the brain. | |
| Ryu and McLarnon (2009)78 | Co-administration of Aβ42 and fibrinogen cause pronounced neuroinflammation which can be reduced by blocking microglial activation | |
| Bailey et al. (2004)82 | Review of the contributions of microvascular pathology to AD | |
| Nelson et al. (2017)85, Shibata et al. (2000)84 | Aβ influx/efflux is dependent on BBB RAGE and LRP1/2 | |
| Zlokovic (2013)92 | Review of the cerebrovascular effects of APOE4 | |
| Main et al. (2018)95 | BBB regeneration is impaired by APOE4 following traumatic brain injury | |
| Alata et al. (2015)96 | APOE4 mice display decreased cerebral vascularization and glucose transport across the BBB | |
| Zipser et al. (2007)100 | Prothrombin levels in the cortex correlate with Braak stage |
Abbreviations: Aβ, beta amyloid protein; AD, Alzheimer’s disease; APOE, apolipoprotein E; BBB, blood–brain barrier; DIO, diet-induced obese; HFD, high-fat diet; HPC, hematopoietic progenitor cell; IR, insulin resistance; LRP, low density lipoprotein receptor; MMP, metalloproteinase; PDFGR, platelet-derived growth factor receptor; RAGE, receptor for advanced glycation end-products; T2DM, type 2 diabetes; TJ, tight junction.