Association of prion protein with cognitive functioning in humans ☆ Lutz Philipp Breitling a, ⁎, Heiko Müller a , Christa Stegmaier b , Matthias Kliegel c , Hermann Brenner a a Division of Clinical Epidemiology and Aging Reseach, German Cancer Research Center, Heidelberg, Germany b Saarland Cancer Registry, Saarbrücken, Germany c Department of Psychology, University of Geneva, Switzerland abstract article info Article history: Received 10 March 2012 Received in revised form 5 July 2012 Accepted 3 August 2012 Available online 8 August 2012 Section Editor: R. Westendorp Keywords: Prion protein Epidemiological study Homo sapiens Cognition Executive function Objectives: Recent animal studies have suggested a key role for cellular prion protein (PrPc) in the pathological consequences of amyloid plaque formation, the hallmark of Alzheimer's disease. This epidemiological study investigated whether serum concentrations of PrPc are associated with cognitive functioning in humans. Design, Setting, Participants: Cross-sectional study of 1,322 participants from the elderly general population in Germany, aged 65+ years at baseline (2000–2002). Measurements: Cognitive functioning was assessed by the COGTEL phone interview 5 years after baseline. Serum PrPc was determined by a commercial immunoassay. Results: In multiple linear regression adjusted for important confounders, subjects in higher PrPc quintiles appeared to have lower cognitive functioning scores than those in the lowest PrPc quintile. Spline regression suggested pronounced non-linearity with an inverse association between PrPc and cognitive functioning levelling off beyond median PrPc. Cognitive subdomain-specific models produced somewhat heterogeneous results. Conclusion: The findings are suggestive of an independent association of PrPc with cognitive functioning in humans. Confirmatory and longitudinal studies are needed to elucidate the potential of PrPc for applications in early risk stratification for cognitive impairment. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Dementias of the Alzheimer type and non-Alzheimer dementias are among the major challenges to aging societies in the early 21st century (Duron and Hanon, 2008). Cellular prion protein (PrP c ) has recently been suggested to be involved in the deleterious conse- quences of amyloid-β build-up (Lauren et al., 2009), the hall-mark of Alzheimer's disease. The data primarily coming out of studies in PrP c knock-out mice suggest that PrP c is an important amyloid-β receptor relevant to the adverse effects of amyloid-β oligomers at the neural synapsis, and research into the clinical relevance of these findings must be considered rather urgent (Cisse and Mucke, 2009). Subse- quent studies have shown that PrP c may also be involved in mediating neurotoxicity of various other β-sheet-rich molecules, suggesting a potential role in pathologies beyond prion disease and Alzheimer's (Resenberger et al., 2011). In the meantime, the PrP c mechanism in Alzheimer's disease has been questioned by some investigators (Balducci et al., 2010; Kessels et al., 2010), but supported by others Bate and Williams (2011), who suggested differences in amyloid-β preparations and memory assess- ments as possible explanations for these discrepancies. Data on the potential association of PrP c with dementia or cognitive functioning in humans remains extremely scarce. One study revealed no associa- tion between brain expression of PrP c and Alzheimer's disease (Saijo et al., 2011), whereas another study found such differences in sporadic cases of Alzheimer's compared to controls (Whitehouse et al., 2010). Thus, although the role of PrP c in Alzheimer's pathology remains con- troversial, it is warranted to consider PrP c a tentative candidate bio- marker for studies of cognitive functioning in humans. Interventions to maintain cognitive functioning are considered to have potential especially during the very early stages of cognitive decline. The present epidemiological study thus focussed on older subjects from the general population, who were characterised using the Cognitive Telephone Screening Instrument (COGTEL). COGTEL was purposely designed to assess cognition across the full range of adult functioning with a broad coverage of diverse cognitive domains (Breitling et al., 2010; Kliegel et al., 2007). The abundance of PrP c was determined in peripheral blood samples, the most relevant Experimental Gerontology 47 (2012) 919–924 ☆ Funding sources: Funded in part by the Baden-Württemberg Ministry of Research, Science and Arts, by the Marsilius Kolleg, Center of Advanced Studies, University of Heidelberg, and by the Federal Ministry for Education and Research (BMBF). Posters related to this work have been presented at the “Forschungstag Lebenswissenschaften der Baden-Württemberg Stiftung”, Heidelberg, 2011, and at the meeting of the German epidemiological society, Mainz, 2011. ⁎ Corresponding author at: Clinic for Gastroenterology, Hepatology and Infectiology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Tel.: +49 221 81 18713; fax: +49 221 81 18752. E-mail address: lutzphilipp.breitling@med.uni-duesseldorf.de (L.P. Breitling). 0531-5565/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.exger.2012.08.001 Contents lists available at SciVerse ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero