Tanzi, Rudolph E

Molecular Neurodegeneration

Harvard University - DASH 

 Decoding Alzheimer’s in the age of genome-wide analyses  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Tanzi, Rudolph E. 2013. “Decoding Alzheimer’s in the age ofgenome-wide analyses.” Molecular Neurodegeneration 8 (Suppl1): O1. doi:10.1186/1750-1326-8-S1-O1.http://dx.doi.org/10.1186/1750-1326-8-S1-O1.Published Version doi:10.1186/1750-1326-8-S1-O1Accessed February 19, 2015 3:05:40 PM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879442Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAORAL PRESENTATION Open AccessDecoding Alzheimer’s in the age of genome-wideanalysesRudolph E TanziFrom Molecular Neurodegeneration: Basic biology and disease pathwaysCannes, France. 10-12 September 2013Alzheimer’s disease (AD) is strongly influenced bygenetic factors as evidenced by numerous family andtwin studies. Over the past two decades, others and wehave co-discovered three early-onset familial AD genes,APP, PSEN1, and PSEN2, which can carry any of >200fully penetrant mutations characterized by mendelianinheritance. For late-onset AD, the most prevalent andhighest impact risk factor is the epsilon 4 variant ofAPOE, which increases risk by 3.7-fold in the heterozy-gous state and >10-fold when two copies are inherited.As part of our Alzheimer’s Genome Project funded bythe Cure Alzheimer’s Fund and the NIMH, we havebeen identifying novel AD candidate genes. In Bertramet al. (2008), we reported genome-wide association ofAD with several loci including the spinocerebellar ataxia 1gene, ATXN1, and the SIGLEC3 gene, CD33. Functionalstudies of the ATXN1 gene carried out both in vitro and invivo in ATXN1 knockout mice show that ATXN1 canregulate Ab levels via modulation of b-secretase. CD33 isjust one of several genes (TREM2, CR1, etc) involved inthe innate immune system of the brain that have beenassociated with AD risk. In addition, we discovered asso-ciation of AD with ADAM10, which encodes the majora-secretase in the brain. Re-sequencing of this gene in thebest associated AD families led to two rare mutations thattightly co-segregated with AD in seven (of 1000) ADfamilies screened, all with average age of onset ~70 years.We have shown both mutations to impair ADAM10 non-amyloidogenic cleavage of APP in vitro and in transgenicmice, including double trangenics with AD (tg2576) mice.Thus, these are the first rare, highly penetrant mutationsreported for late-onset AD. We have also carried out gen-ome-wide association studies on >800 well-characterizedlate-onset AD families (NIMH and NIA-LOAD samples)using Affymetrix genotyping arrays containing either onemillion (6.0) or 20,000 coding SNPs. More recently, wehave performed whole genome sequencing (Illumina,Hiseq) on over 1500 samples from AD families/sibships.The elucidation of the genes and functional variantsinfluencing risk for AD should continue to enhanceour understanding of AD etiology and pathogenesis.Ultimately, these genes will be used to predict risk for ADand guide novel the development of therapies for the effec-tive treatment and prevention of this terrible disease.Published: 13 September 2013doi:10.1186/1750-1326-8-S1-O1Cite this article as: Tanzi: Decoding Alzheimer’s in the age ofgenome-wide analyses. Molecular Neurodegeneration 2013 8(Suppl 1):O1.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitMassachusetts General Hospital/Harvard Medical School, Charlestown, MA,USATanzi Molecular Neurodegeneration 2013, 8(Suppl 1):O1http://www.molecularneurodegeneration.com/content/8/S1/O1© 2013 Tanzi; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

Decoding Alzheimer’s in the age of genome-wide analyses

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Decoding Alzheimer’s in the age of genome-wide analyses

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