Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology

Article type: Research Article

Authors: Kleinschmidt, Martin^{a; c; *} | Schoenfeld, Robby^b | Göttlich, Claudia^{a; f} | Bittner, Daniel^d | Metzner, Jürgen Erich^e | Leplow, Bernd^b | Demuth, Hans-Ulrich^{a; c; *}

Affiliations: [a] Probiodrug AG, Halle (Saale), Germany | [b] Martin-Luther-University Halle-Wittenberg, Department of Psychology, Halle (Saale), Germany | [c] Current address: Fraunhofer Institute of Cell Therapy and Immunology, Department of Drug Design and Target Validation, Halle (Saale), Germany | [d] Clinic for Neurology, Otto-von-Guericke University Magdeburg, Germany | [e] Galmed GmbH, Halle (Saale), Germany | [f] Department Tissue Engineering & Regenerative Medicine (TERM), University Hospital Wuerzburg, Germany

Correspondence: [*] Correspondence to: Dr. Martin Kleinschmidt, Fraunhofer Institute for Cell Therapy and Immunology IZI, Weinbergweg 22, 06120 Halle (Saale), Germany. Tel.: +49 345 13142827; Fax: +49 345 13142801; E-mail: [email protected].

Correspondence: [*] Correspondence to: Prof. Hans-Ulrich Demuth, Fraunhofer Institute for Cell Therapy and Immunology IZI, Weinbergweg 22, 06120 Halle (Saale), Germany. Tel.: +49 345 13142805; Fax: +49 345 13142801; E-mail: [email protected].

Abstract: Background:Current treatment in Alzheimer’s disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. Objective:The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. Methods:In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively. Results:Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ. Conclusion:Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.

Keywords: Aging, Alzheimer’s disease, amyloid-β, ApoE, autoantibodies, blood, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-143189

Journal: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 111-126, 2016