Sanchez-Mut JV Heyn H Silva BA Dixsaut L Garcia-Esparcia P Vidal E Sayols S Glauser L Monteagudo-Sánchez A Perez-Tur J Ferrer I Monk D Schneider B Esteller M Gräff J 2018 The chances to develop Alzheimer's disease (AD) result from a combination of genetic and non-genetic risk factors 1 , the latter likely being mediated by epigenetic mechanisms 2 . In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology 3 , but a causal relationship remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations, which provide mechanistic insights for a particular risk gene but often lack the statistical power of GWAS 4 . Here, combining both approaches, we report a previously unidentified association of the peptidase M20-domain-containing protein 1 (PM20D1) with AD. We find that PM20D1 is a methylation and expression quantitative trait locus coupled to an AD-risk associated haplotype, which displays enhancer-like characteristics and contacts the PM20D1 promoter via a haplotype-dependent, CCCTC-binding-factor-mediated chromatin loop. Furthermore, PM20D1 is increased following AD-related neurotoxic insults at symptomatic stages in the APP/PS1 mouse model of AD and in human patients with AD who are carriers of the non-risk haplotype. In line, genetically increasing or decreasing the expression of PM20D1 reduces and aggravates AD-related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD. https://sonar.ch/global/documents/102661 eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41591-018-0013-y info:eu-repo/semantics/altIdentifier/pmid/29736028 Nature medicine. - 2018 Aged Alzheimer Disease Amidohydrolases Amyloid beta-Peptides Animals Cell Line, Tumor Chromatin Female Frontal Lobe Genome-Wide Association Study Humans Hydrogen Peroxide Linkage Disequilibrium Male Mice Middle Aged Polymorphism, Single Nucleotide Quantitative Trait Loci PM20D1 is a quantitative trait locus associated with Alzheimer's disease. http://purl.org/coar/resource_type/c_6501