Blood‐brain barrier permeability measured by 7α‐hydroxy‐3‐oxo‐4‐cholestenoic acid in CSF associates with Alzheimer's pathology biomarkers in cerebrospinal fluid: Biomarkers (non‐neuroimaging) / Novel biomarkers. (7th December 2020)

• Record Type: Journal Article
• Authors: Heston, Margo B.; Vogt, Nicholas M.; Kohli, Akshay; Sun, Yi; Kerby, Robert L.; Carlsson, Cynthia M.; Engelman, Corinne D.; Johnson, Sterling C.; Asthana, Sanjay; Ulland, Tyler; Blennow, Kaj; Zetterberg, Henrik; Rey, Federico E.; Bendlin, Barbara B.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.046582
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The intestinal microbiota may modulate Alzheimer's disease (AD), however the mechanisms by which it impacts the brain remain unknown. A leading proposal suggests that altered gut permeability promotes systemic inflammation, which may impact blood‐brain barrier (BBB) and exacerbate AD pathology. To test this hypothesis, we performed analyses on levels of 7α‐hydroxy‐3‐oxo‐4‐cholestenoic acid (7‐HOCA), a potential BBB permeability marker, calprotectin in stool, a gastrointestinal inflammation marker, and cerebrospinal fluid biomarkers of AD pathology. We tested for differences in BBB by cognitive diagnosis, associations with AD biomarkers in CSF, and potential mediation by calprotectin. Method: CSF was collected via lumbar puncture from participants in the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center [CU (N=334), AD mild cognitive impairment (MCI) (N=35), AD dementia (N=40)]. Stool samples from 25 of these participants [CU (N=16), AD (N=9)] were additionally analyzed for calprotectin levels (ELISA, Eagle Biosciences). 7‐HOCA relative abundance in CSF and plasma was measured via Metabolon's UHPLC/MS metabolomics platform. CSF biomarkers included Aβ42/Aβ40, NfL, pTau, tTau, YKL‐40 and neurogranin. Multiple linear regressions (R) were performed across 7‐HOCA, calprotectin and AD biomarkers controlling for age, sex and APOE ε4 carrier status. Result: 7‐HOCA levels in CSF were significantly increased in AD compared with CU participants (Figure 1). pTau/Aβ42 was significantly negatively associated with 7‐HOCA (Figure 2), while pTau, tTau, YKL‐40, NfL, and neurogranin were significantly positively associated with 7‐HOCA levels. Aβ42/Aβ40 was not associated with 7‐HOCA. Elevated calprotectin associated with CSF amyloid positivity (Figure 3), but due to small sample size this did not meet statistical significance. No significant associations were found with plasma 7‐HOCA, or with calprotectin moderating the biomarker/7‐HOCA relationships. Conclusion: 7‐HOCA is elevated in AD dementia, and is associated with markers of AD, neurodegeneration, and glia activation measured in CSF, potentially suggesting altered BBB in AD. While model coefficients suggest relationships between AD biomarkers and the calprotectin*7‐HOCA interaction term, the results were not significant, likely due to the small N for calprotectin analyses. Additional analyses are needed to determine whether the effects of gut microbiota on brain may be mediated by altered intestinal and BBB permeability.