A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Authors:
Dr.  Sonja Scholz, MD, PhD
Dr. Sonja Scholz, MD, PhD
National Institute of Neurological Disorders and Stroke
Lasker Clinical Research Scholar
Neurology
Bethesda, MD | United States
Sven J van der Lee Olivia J Conway Iris Jansen Minerva M Carrasquillo Luca Kleineidam Erik van den Akker Isabel Hernández Kristel R van Eijk Najada Stringa Jason A Chen Anna Zettergren Till F M Andlauer Monica Diez-Fairen Javier Simon-Sanchez Alberto Lleó Henrik Zetterberg Marianne Nygaard Cornelis Blauwendraat Jeanne E Savage Jonas Mengel-From Sonia Moreno-Grau Michael Wagner Juan Fortea Michael J Keogh Kaj Blennow Ingmar Skoog Manuel A Friese Olga Pletnikova Miren Zulaica Carmen Lage Itziar de Rojas Steffi Riedel-Heller Ignacio Illán-Gala Wei Wei Bernard Jeune Adelina Orellana Florian Then Bergh Xue Wang Marc Hulsman Nina Beker Niccolo Tesi Christopher M Morris Begoña Indakoetxea Lyduine E Collij Martin Scherer Estrella Morenas-Rodríguez James W Ironside Bart N M van Berckel Daniel Alcolea Heinz Wiendl Samantha L Strickland Pau Pastor Eloy Rodríguez Rodríguez Bradley F Boeve Ronald C Petersen Tanis J Ferman Jay A van Gerpen Marcel J T Reinders Ryan J Uitti Lluís Tárraga Wolfgang Maier Oriol Dols-Icardo Amit Kawalia Maria Carolina Dalmasso Mercè Boada Uwe K Zettl Natasja M van Schoor Marian Beekman Mariet Allen Eliezer Masliah Adolfo López de Munain Alexander Pantelyat Zbigniew K Wszolek Owen A Ross Dennis W Dickson Neill R Graff-Radford David Knopman Rosa Rademakers Afina W Lemstra Yolande A L Pijnenburg Philip Scheltens Thomas Gasser Patrick F Chinnery Bernhard Hemmer Martijn A Huisman Juan Troncoso Fermin Moreno Ellen A Nohr Thorkild I A Sørensen Peter Heutink Pascual Sánchez-Juan Danielle Posthuma Jordi Clarimón Kaare Christensen Nilüfer Ertekin-Taner Sonja W Scholz Alfredo Ramirez Agustín Ruiz Eline Slagboom Wiesje M van der Flier Henne Holstege

Acta Neuropathol 2019 Aug 27;138(2):237-250. Epub 2019 May 27.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

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http://dx.doi.org/10.1007/s00401-019-02026-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660501PMC
August 2019
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