Autoantibodies Toward the Angiotensin 2 Type 1 Receptor: A Novel Autoantibody in Alzheimer’s Disease
Authors: Giil, Lasse M. | Kristoffersen, Einar K. | Vedeler, Christian A. | Aarsland, Dag | Nordrehaug, Jan Erik | Winblad, Bengt | Cedazo-Minguez, Angel | Lund, Anders | Reksten, Tove Ragna
Article Type: Research Article
Abstract: Background: Autoantibodies with agonist function are described in cardiovascular disorders. Since vascular risk factors are associated with an increased risk for Alzheimer’s disease (AD), we investigated a potential association between antibodies to the angiotensin 2 type 1 receptor (anti-AT1R) and AD. Objective: The primary objective of this study was to investigate the association between anti-AT1R and AD. The secondary objective was to investigate the association between clinical or biomarker features of AD and anti-AT1R. Methods: Samples from patients with mild AD participating in a longitudinal study in Western Norway (n = 92, 65 [71%] females, mean age 74.8 [range 50–89]) and …age- and gender-matched healthy controls (n = 102) were included. Cerebrospinal fluid (CSF) AD biomarkers were assessed in a subgroup of patients. Patients were examined annually, including Mini-Mental State Examination. ELISA was used to measure anti-AT1R in serum. Non-parametric tests were used for statistical calculations and a p < 0.05 was considered significant. Results: AD patients had significantly higher levels of anti-AT1R compared with healthy controls (10.2 U/mL versus 8.1 U/mL, p = 0.04). This difference was found only in patients without hypertension and diabetes. Anti-AT1R levels correlated with CSF total tau (p = 0.03) and phosphorylated tau (p = 0.03) levels, and inversely with blood pressure in AD (Spearman R −0.277, p = 0.008). Discussion: AD is associated with increased levels of anti-AT1R, and the antibodies correlated with CSF total, and phosphorylated tau levels. Further research is needed to understand the blood pressure response in AD without hypertension and a potential link between tau and anti-AT1R in AD. Show more
Keywords: AT1R, autoimmunity, dementia, neurodegeneration
DOI: 10.3233/JAD-150053
Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 523-529, 2015
Authors: Giil, Lasse M. | Vedeler, Christian A. | Kristoffersen, Einar K. | Nordrehaug, Jan Erik | Heidecke, Harald | Dechend, Ralf | Schulze-Forster, Kai | Muller, Dominik N. | von Goetze, Victoria S. | Cabral-Marques, Otavio | Riemekasten, Gabriela | Vogelsang, Petra | Nygaard, Staale | Lund, Anders | Aarsland, Dag
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is associated with several antibodies as well as signaling molecules and receptors. These may be detrimental in the presence of a disrupted blood-brain barrier (BBB). Objective: To investigate whether the levels of antibodies toward 33 signaling molecules involved in neurotransmitter, vascular, and immune functions were associated with AD and, within the AD group; cognitive function and mood. Methods: Antibodies in sera from patients with mild AD [(n = 91) defined as a Mini-Mental State Examination ≥ 20 or a Clinical Dementia Rating Scale≤1] and healthy controls (n = 102) were measured with enzyme-linked immunosorbent assays. Levels in AD …and controls were compared by Mann-Whitney test. In the AD group, associations between antibodies and psychometric test scores were analyzed by robust regression. The false discovery threshold was set to 0.05. Results: Antibodies to serotonin receptors [5-HT2A R (effect size (r) = 0.21, p = 0.004), 5-HT2C R (r = 0.25, p = 0.0005) and 5-HT7 R (r = 0.21, p = 0.003)], vascular endothelial growth factor receptor 1 [VEGFR1 (r = 0.29, p < 0.001)] and immune-receptors (Stabilin-1 (r = 0.23, p = 0.001) and C5aR1 (r = 0.21, p = 0.004) were higher in AD. Psychomotor speed was associated with D1 R-abs (β 0.49, p < 0.001), depression with ETAR-abs (β 0.31, p < 0.001), and visuospatial function with 5-HT1A R-abs (β 0.27, p = 0.004) despite similar antibody levels compared to controls. Conclusions: Antibody levels to VEGFR1, serotonergic receptors, and receptors in the immune system were increased in AD. Antibodies at similar levels as in controls were associated cognitive dysfunction and depression in AD. Show more
Keywords: C5aR, 5-HT2AR, 5-HT2CR, 5-HT7R, MADRS, naturally occurring antibodies, Stablin-1, Trail Making A, VEGFR1, VOSP
DOI: 10.3233/JAD-170245
Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 929-939, 2017
Authors: Giil, Lasse M. | Aarsland, Dag | Hellton, Kristoffer | Lund, Anders | Heidecke, Harald | Schulze-Forster, Kai | Riemekasten, Gabriela | Vik-Mo, Audun Osland | Kristoffersen, Einar K. | Vedeler, Christian A. | Nordrehaug, Jan Erik
Article Type: Research Article
Abstract: Background: Endogenous antibodies to signaling molecules and receptors (Abs) are associated with Alzheimer’s disease (AD). Objectives: To investigate the association of 33 Abs to dopaminergic, serotoninergic, muscarinic, adrenergic, vascular, and immune receptors with cognitive, neuropsychiatric, and mortality outcomes. Methods: Ninety-one patients with mild AD were followed annually for 5 years with the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI; composite outcomes: “psychosis” (item 1 + 2), “mood” (item 4 + 5 + 7), and “agitation” (item 3 + 8 + 9)). Abs were quantified in sera obtained at baseline by ELISA and reduced to principal components (PCs). Associations …between Abs and outcomes were assessed by a mixed model (MMSE decline), zero-inflated fixed effects count models (composite NPI scores), and Cox regression (mortality). The resulting p -values were adjusted for multiple testing according to a false discovery rate of 0.05 (Benjamini-Hochberg). Results: The measured levels of the 33 Abs formed four PCs. PC1 (dopaminergic and serotonergic Abs) was associated with increased mortality (Hazard ratio 2.57, p < 0.001), PC2 (serotonergic, immune, and vascular Abs) with decreased agitation symptoms (β – 0.19, p < 0.001), and PC3 (cholinergic receptor Abs) with increased mood symptoms (β 0.04, p = 0.002), over time. There were no associations between Abs and MMSE decline. Conclusion: The associations between Abs, mortality, and neuropsychiatric symptoms reported in this cohort are intriguing. They cannot, however, be generalized. Validation in independent sample sets is required. Show more
Keywords: Dopaminergic, naturally occurring antibodies, neuropsychiatric inventory, neuropsychiatric symptoms, physiological antibodies, serotonergic
DOI: 10.3233/JAD-170882
Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 761-774, 2018
