Mutation Analysis of the Genes Linked to Early Onset Alzheimer’s Disease and Frontotemporal Lobar Degeneration

Article type: Research Article

Authors: Luukkainen, Laura^{a; b} | Helisalmi, Seppo^c | Kytövuori, Laura^{a; b} | Ahmasalo, Riitta^d | Solje, Eino^{c; e} | Haapasalo, Annakaisa^f | Hiltunen, Mikko^g | Remes, Anne M.^{a; b; *} | Krüger, Johanna^{a; b}

Affiliations: [a] Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland | [b] MRC, Oulu University Hospital, Oulu, Finland | [c] Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland | [d] Department of Neurology, Lapland Central Hospital, Rovaniemi, Finland | [e] Neuro Center, Neurology, Kuopio University Hospital, Kuopio, Finland | [f] A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland | [g] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

Correspondence: [*] Correspondence to: Anne M. Remes, MD, PhD, Professor, Dean, Faculty of Medicine, University of Oulu, Aapistie 5 A, FIN-90230 Oulu, Finland. Tel.: +358 50 533 0090; E-mail: [email protected].

Abstract: A lot of effort has been done to unravel the genetics underlying early-onset Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). However, many familial early-onset dementia (EOD) cases still show an unclear genetic background. The aim of this study was to evaluate the role of the known causative mutations and possible pathogenic variants associated with AD and FTLD in a Finnish EOD cohort. The cohort consisted of 39 patients (mean age at onset 54.8 years, range 39–65) with a positive family history of dementia or an atypical or rapidly progressive course of the disease. None of the patients carried the C9orf72 hexanucleotide repeat expansion. Mutations and variants in APP, PSEN1, PSEN2, MAPT, GRN, VCP, CHMP2B, FUS, TARDBP, TREM2, TMEM106B, UBQLN2, SOD1, PRNP, UBQLN1, and BIN1 were screened by using a targeted next generation sequencing panel. Two previously reported pathogenic mutations (PSEN1 p.His163Arg and MAPT p.Arg406Trp) were identified in the cohort. Both patients had familial dementia with an atypical early onset phenotype. In addition, a heterozygous p.Arg71Trp mutation in PSEN2 with an uncertain pathogenic nature was identified in a patient with neuropathologically confirmed AD. In conclusion, targeted investigation of the known dementia-linked genes is worthwhile in patients with onset age under 55 and a positive family history, as well as in patients with atypical features.

Keywords: Alzheimer’s disease, early onset, frontotemporal dementia, frontotemporal lobar degeneration, genetics, human, microtubule-associated protein tau, missense, mutation, presenilin-1

DOI: 10.3233/JAD-181256

Journal: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 775-782, 2019