Effects of Alzheimer's Disease-Associated Risk Loci on Cerebrospinal Fluid Biomarkers and Disease Progression: A Polygenic Risk Score Approach

Article type: Research Article

Authors: Martiskainen, Henna^{a; 1} | Helisalmi, Seppo^{a; 1} | Viswanathan, Jayashree^a | Kurki, Mitja^{b; c} | Hall, Anette^a | Herukka, Sanna-Kaisa^a | Sarajärvi, Timo^a | Natunen, Teemu^a | Kurkinen, Kaisa M.A.^a | Huovinen, Jaakko^a | Mäkinen, Petra^a | Laitinen, Marjo^a | Koivisto, Anne M.^a | Mattila, Kari M.^d | Lehtimäki, Terho^d | Remes, Anne M.^a | Leinonen, Ville^{b; c} | Haapasalo, Annakaisa^a | Soininen, Hilkka^a | Hiltunen, Mikko^{a; e; *}

Affiliations: [a] Institute of Clinical Medicine – Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland | [b] Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland | [c] Institute of Clinical Medicine – Neurosurgery, University of Eastern Finland, Kuopio, Finland | [d] Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland | [e] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

Correspondence: [*] Correspondence to: Mikko Hiltunen, PhD, Institute of Clinical Medicine – Neurology, University of Eastern Finland, P.O. Box 1627, FIN-70211, Kuopio, Finland. Tel.: +358 40 355 2014; Fax: +358 17 162048; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis. Objective:To investigate the individual and combined risk effects of the newly identified AD loci. Methods:Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex. Results:Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-ε4 associated with CSF Aβ42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction. Conclusions:AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.

Keywords: Alzheimer's disease, amyloid-β peptide, biomarker, cerebrospinal fluid, polygenic risk score, risk gene, tau protein

DOI: 10.3233/JAD-140777

Journal: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 565-573, 2015