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Int J Mol Epidemiol Genet 2012;3(1):30-38

Original Article
Genetic variation in MME in relation to neprilysin protein and enzyme activity,
Aβ levels, and Alzheimer’s disease risk

Scott Miners, Zoë van Helmond, Rachel Barker, Peter A Passmore, Janet A Johnston, Stephen Todd, Bernadette M
McGuinness, Francesco Panza, Davide Seripa, Vincenzo Solfrizzi, Seth Love, Jonathan A Prince, Patrick G Kehoe

Dementia Research Group, University of Bristol, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK; Department
of Geriatric Medicine, The Queen’s University of Belfast, Belfast, UK; Department of Geriatrics, Center for Aging Brain, Memory
Unit, University of Bari, Bari, Italy; Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical
Sciences, IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy; Center for Genomics and
Bioinformatics, Karolinska Institute, Stockholm, Sweden

Received November 29, 2011; accepted December 12, 2011; Epub February 5, 2012; Published February 28, 2012

Abstract: Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most
important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer’s disease (AD) pathology. Variation in the
NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs –
rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057
probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden.
We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical
measures of Aβ accumulation in frontal cortex – levels of total soluble Aβ, oligomeric Aβ1-42, and guanidine-extractable
(insoluble) Aβ – in sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression
analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95%
confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly
associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and
NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data
suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through
modification of NEP protein level or activity. (IJMEG1111009).

Keywords: Neprilysin, MME, gene, association, β-Amyloid, alzheimer disease, polymorphism

Address all correspondence to:
Dr. Patrick G Kehoe
Dementia Research Group, John James Laboratories
School of Clinical Sciences, University of Bristol
Day Hospital, Frenchay Hospital, Bristol, BS16 1LE, UK.
Tel: +44-117-340-3070; Fax: +44-117-340-6665
E-mail: Patrick.Kehoe@bristol.ac.uk