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Am J Neurodegener Dis 2013;2(3):145-175

Review Article
Pathways to neurodegeneration: mechanistic insights from GWAS in
Alzheimer’s disease, Parkinson’s disease, and related disorders

Vijay K Ramanan, Andrew J Saykin

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine,
Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine,
Indianapolis, IN, USA; Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA;
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA;
Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA

Received July 11, 2013; Accepted August 25, 2013; Epub September 18, 2013; Published September 30, 2013

Abstract: The discovery of causative genetic mutations in affected family members has historically dominated our
understanding of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD),
frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of
neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are
thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility.
Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative
diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial
overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-
implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on
individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which
traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have
focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks
revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes
may be influenced on a personalized basis by a combination of variants – some common and others rare, some
protective and others deleterious – in key genes and pathways. Here, we review and synthesize the major pathways
implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and
PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated
genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven
model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other
neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require
simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and
modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from
GWAS and other modalities to enhance clinical translation. (AJND1307002).

Keywords: Neurodegeneration, Alzheimer’s disease (AD), Parkinson’s disease (PD), genome-wide association study
(GWAS), single nucleotide polymorphism (SNP), pathway, network, biomarker, omics, complex disease

Address correspondence to: Dr. Andrew J Saykin, IU Health Neuroscience Center, Suite 4100, Indiana University
School of Medicine, 355 West 16th Street, Indianapolis, IN 46202, USA. Tel: 317-963-7501; Fax: 317-963-7547; E-mail: