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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

Journal article
Authors S. J. van der Lee
O. J. Conway
I. Jansen
M. M. Carrasquillo
L. Kleineidam
E. van den Akker
I. Hernandez
K. R. van Eijk
N. Stringa
J. A. Chen
Anna Zettergren
T. F. M. Andlauer
M. Diez-Fairen
J. Simon-Sanchez
A. Lleo
H. Zetterberg
M. Nygaard
C. Blauwendraat
J. E. Savage
J. Mengel-From
S. Moreno-Grau
M. Wagner
J. Fortea
M. J. Keogh
Kaj Blennow
I. Skoog
M. A. Friese
O. Pletnikova
M. Zulaica
C. Lage
I. de Rojas
S. Riedel-Heller
I. Illan-Gala
W. Wei
B. Jeune
A. Orellana
F. T. Bergh
X. Wang
M. Hulsman
N. Beker
N. Tesi
C. M. Morris
B. Indakoetxea
L. E. Collij
M. Scherer
E. Morenas-Rodriguez
J. W. Ironside
B. N. M. van Berckel
D. Alcolea
H. Wiendl
S. L. Strickland
P. Pastor
E. Rodriguez Rodriguez
B. F. Boeve
R. C. Petersen
T. J. Ferman
J. A. van Gerpen
M. J. T. Reinders
R. J. Uitti
L. Tarraga
W. Maier
O. Dols-Icardo
A. Kawalia
M. C. Dalmasso
M. Boada
U. K. Zettl
N. M. van Schoor
M. Beekman
M. Allen
E. Masliah
A. L. de Munain
A. Pantelyat
Z. K. Wszolek
O. A. Ross
D. W. Dickson
N. R. Graff-Radford
D. Knopman
R. Rademakers
A. W. Lemstra
Y. A. L. Pijnenburg
P. Scheltens
T. Gasser
P. F. Chinnery
B. Hemmer
M. A. Huisman
J. Troncoso
F. Moreno
E. A. Nohr
T. I. A. Sorensen
P. Heutink
P. Sanchez-Juan
D. Posthuma
J. Clarimon
K. Christensen
N. Ertekin-Taner
S. W. Scholz
A. Ramirez
A. Ruiz
E. Slagboom
W. M. van der Flier
H. Holstege
Published in Acta Neuropathologica
Volume 138
Issue 2
Pages 237-250
ISSN 0001-6322
Publication year 2019
Published at Institute of Neuroscience and Physiology
Centre for Ageing and Health (Agecap)
Pages 237-250
Language en
Keywords Alzheimer's disease, Frontotemporal dementia, Dementia with Lewy bodies, Progressive supranuclear palsy, Parkinson's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, Neurodegenerative disease, Longevity, PLCG2, Phospholipase C Gamma 2, genome-wide association, phospholipase-c-gamma, genetic architecture, innate immunity, activation, apoe, autoimmunity, inflammation, replication, mechanisms, Neurosciences & Neurology, Pathology
Subject categories Neurosciences


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 PLC gamma 2 pathway as drug-target.

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