AUTHOR=Gan Jinghuan , Yang Xia , Zhang Guili , Li Xudong , Liu Shuai , Zhang Wei , Ji Yong 

TITLE=Alzheimer's disease pathology: pathways between chronic vascular risk factors and blood-brain barrier dysfunction in a cohort of patients with different types of dementia

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=15

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1088140

DOI=10.3389/fnagi.2023.1088140

ISSN=1663-4365

ABSTRACT=<sec><title>Background</title><p>Blood brain barrier (BBB) breakdown is considered a potential mechanism of dementia. The Alzheimer's disease (AD) biomarkers and vascular factors are also associated with BBB permeability.</p></sec><sec><title>Objective</title><p>In the present study, the combination effects of neuropathological biomarkers of AD and chronic vascular risk factors for BBB were investigated.</p></sec><sec><title>Methods</title><p>The cerebrospinal fluid (CSF)/serum albumin ratio (Qalb), an indicator of BBB permeability, was measured in a total of 95 hospitalized dementia patients. The demographics, clinical information, and laboratory tests were collected from the inpatient records. The CSF neuropathological biomarkers of AD and apolipoprotein E (APOE) genotype were also collected. The mediation analysis model was used to calculate the associations among neuropathological biomarkers of AD (mediator), the Qalb, and chronic vascular risk factors.</p></sec><sec><title>Results</title><p>Three types of dementia, AD (<italic>n</italic> = 52), Lewy body dementia (LBD, <italic>n</italic> = 19), and frontotemporal lobar degeneration (<italic>n</italic> = 24), were included with a mean Qalb of 7.18 (± 4.36). The Qalb was significantly higher in dementia patients with type 2 diabetes mellitus (T2DM, <italic>p</italic> = 0.004) but did not differ based on the presence of APOE ε4 allele, CMBs, or amyloid/tau/neurodegeneration (ATN) framework. The Qalb was negatively associated with the levels of Aβ1-42 (B = −20.775, <italic>p</italic> = 0.009) and Aβ1-40 (B = −305.417, <italic>p</italic> = 0.005) and positively associated with the presence of T2DM (B = 3.382, <italic>p</italic> &lt; 0.001) and the levels of glycosylated hemoglobin (GHb, B = 1.163, <italic>p</italic> &lt; 0.001) and fasting blood glucose (FBG, B = 1.443, <italic>p</italic> &lt; 0.001). GHb is a direct chronic vascular risk factor for higher Qalb (total effect B = 1.135, 95% CI: 0.611–1.659, <italic>p</italic> &lt; 0.001). Ratios of Aβ1-42/Aβ1-40 or t-tau/Aβ1-42 were mediators of the association between the Qalb and GHb; the direct effect of GHb on the Qalb was 1.178 (95% CI: 0.662–1.694, <italic>p</italic> &lt; 0.001).</p></sec><sec><title>Conclusion</title><p>Glucose exposure can directly or indirectly affect BBB integrity through Aβ and tau, indicating glucose affects BBB breakdown and glucose stability plays an important role in dementia protection and management.</p></sec>