title: Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk.
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 Aβ(1-42), and guanidine-extractable (insoluble) Aβ - in a 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.
authors.affiliation: Dementia Research Group, University of Bristol, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Miners
authors.forename: Zoë
authors.initials: Z
authors.lastname: van Helmond
authors.forename: Rachel
authors.initials: R
authors.lastname: Barker
authors.forename: Peter A
authors.initials: PA
authors.lastname: Passmore
authors.forename: Janet A
authors.initials: JA
authors.lastname: Johnston
authors.forename: Stephen
authors.initials: S
authors.lastname: Todd
authors.forename: Bernadette M
authors.initials: BM
authors.lastname: McGuinness
authors.forename: Francesco
authors.initials: F
authors.lastname: Panza
authors.forename: Davide
authors.initials: D
authors.lastname: Seripa
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Solfrizzi
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Prince
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe