Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease

Eur J Hum Genet. 2015 Oct;23(10):1328-33

Authors/Editors: Eva C Schulte
Brit Mollenhauer
Hyun Hor
Thomas Arzberger
Robert Perneczky
Alexander Kurz
Janine Diehl-Schmid
Michael Hüll
Peter Lichtner
Gertrud Eckstein
Alexander Zimprich
Dietrich Haubenberger
Walter Pirker
Thomas Brücke
Benjamin Bereznai
Maria J Molnar
Oswaldo Lorenzo-Betancor
Pau Pastor
Annette Peters
Christian Gieger
Xavier Estivill
Thomas Meitinger
Hans A Kretzschmar
Claudia Trenkwalder
Christian Haass
Juliane Winkelmann
Publication Date: 2015
Type of Publication: Journal Article

Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.

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