Antibodies to Multiple Receptors are Associated with Neuropsychiatric Symptoms and Mortality in Alzheimer’s Disease: A Longitudinal Study

Article type: Research Article

Authors: Giil, Lasse M.^{a; b; *} | Aarsland, Dag^{c; d} | Hellton, Kristoffer^e | Lund, Anders^b | Heidecke, Harald^f | Schulze-Forster, Kai^f | Riemekasten, Gabriela^g | Vik-Mo, Audun Osland^{b; d} | Kristoffersen, Einar K.^{b; h} | Vedeler, Christian A.^{i; j} | Nordrehaug, Jan Erik^{b; k}

Affiliations: [a] Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway | [b] Department of Clinical Science, University of Bergen, Norway | [c] Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, Kings College, UK | [d] Centre for Age-Related Diseases (SESAM), Stavanger University Hospital, Norway | [e] Norwegian Computing Center, Oslo, Norway | [f] CellTrend GmbH, Luckenwalde, Berlin, Germany | [g] Department of Rheumatology, University Hospital Schleswig-Holstein, Lübeck, Germany | [h] Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway | [i] Department of Clinical Medicine, University of Bergen, Bergen, Norway | [j] Department of Neurology, Haukeland University Hospital, Bergen, Norway | [k] Department of Cardiology, Stavanger University Hospital, Stavanger, Norway

Correspondence: [*] Correspondence to: Lasse Melvaer Giil, MD, Haraldsplass Deaconess Hospital, Ulriksdal 81, 5009, Bergen, Norway. E-mail: [email protected].

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.

Keywords: Dopaminergic, naturally occurring antibodies, neuropsychiatric inventory, neuropsychiatric symptoms, physiological antibodies, serotonergic

DOI: 10.3233/JAD-170882

Journal: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 761-774, 2018