Genetic Analysis of Genes Involved in Amyloid-β Degradation and Clearance in Alzheimer's Disease

Article type: Research Article

Authors: Natunen, Teemu | Helisalmi, Seppo | Vepsäläinen, Saila | Sarajärvi, Timo | Antikainen, Leila | Mäkinen, Petra | Herukka, Sanna-Kaisa | Koivisto, Anne Maria | Haapasalo, Annakaisa | Soininen, Hilkka | Hiltunen, Mikko^{; *}

Affiliations: Institute of Clinical Medicine – Neurology, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, 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 17 162 048; E-mail: [email protected].

Abstract: Accumulation of amyloid β-peptide (Aβ) in the brain of Alzheimer's disease (AD) patients has been postulated to reflect defects in Aβ degradation or clearance. Here, we selected 12 genes (MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9) involved in Aβ catabolism on the basis of PubMed-based literature search and elucidated their genetic role in AD among Finnish case-control cohort consisting of total ∼1,300 AD patients and control subjects. Thirty one single nucleotide polymorphisms (SNPs) were selected for genotyping. In a smaller subset of AD patients, cerebrospinal fluid (CSF) levels of Aβ42 (n = 124), total-tau (n = 59), and phospho-tau (n = 54) analyses were performed with respect to SNPs. Moreover, age of onset analyses with respect to the studied SNPs were conducted among the AD patient cohort (n = 642). Association analysis of the liver X receptor α (NR1H3) gene SNPs showed a protective effect for C allele carriers of rs7120118 (OR = 0.70, 95% CI 0.53–0.93), while the total-tau and phospho-tau levels in CSF were decreased in AD patients carrying the C allele. Also, a decrease in the age of onset was observed in AD patients carrying the A allele of rs723744 and the C allele of rs3794884 in transthyretin (TTR) gene. However, after adjusting the p-values for multiple comparisons, these results were not statistically significant, suggesting that genetic variations in MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9 genes do not play major role among the Finnish AD patient cohort.

Keywords: Alzheimer's disease, Aβ clearance, Aβ degradation, NR1H3, risk gene, TTR

DOI: 10.3233/JAD-2011-111109

Journal: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 553-559, 2012