Effects of Alzheimer’s Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients

Article type: Research Article

Authors: Laiterä, Tiina^{a; b; 1} | Paananen, Jussi^{c; 1} | Helisalmi, Seppo^a | Sarajärvi, Timo^{a; c} | Huovinen, Joel^b | Laitinen, Marjo^a | Rauramaa, Tuomas^{d; e} | Alafuzoff, Irina^f | Remes, Anne M.^a | Soininen, Hilkka^a | Haapasalo, Annakaisa^g | Jääskeläinen, Juha E.^b | Leinonen, Ville^{b; 1; *} | Hiltunen, Mikko^{a; c; 1; *}

Affiliations: [a] Institute of Clinical Medicine – Neurology, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, Kuopio, Finland | [b] Institute of Clinical Medicine – Neurosurgery, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland | [c] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland | [d] Institute of Clinical Medicine – Pathology, University of Eastern Finland and Department of Pathology, Kuopio University Hospital, Kuopio, Finland | [e] Department of Pathology, Kuopio University Hospital, Kuopio, Finland | [f] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden | [g] A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

Correspondence: [*] Correspondence to: Mikko Hiltunen, PhD, Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70210 Kuopio, Finland. Tel.: +358 40 3552014; Fax: +358 17 162048; E-mail: [email protected] and Ville Leinonen, MD PhD, Department of Neurosurgery, Kuopio University Hospital, P. O. Box 100, FI-70029 KYS, Finland. Tel.: +358 44 717 2303; Fax: +358 17 173 916; E-mail: [email protected].

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

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer’s disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects. Objective: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients. Methods: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition. Results: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition. Conclusion: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.

Keywords: Alzheimer’s disease, amyloid-β, apolipoprotein E, genome wide association studies, idiopathic normal pressure hydrocephalus

DOI: 10.3233/JAD-160554

Journal: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 995-1003, 2017