Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

By L. Jones, P. Holmans, M. Hamshere, D. Harold, V. Moskvina, D. Ivanov, A. Pocklington, R. Abraham, P. Hollingworth, R. Sims and 72 more. PLoS ONE, 2010

635 citations recorded by the source corpus.

Background Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Subfields: Genetics, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/bb26f4dd382ce55ca01f9493f79cca30ab82fcd1

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Neurology

1. John Hardy
2. D. Selkoe

In Physiology

1. John Hardy
2. D. Selkoe
3. Jonathan M. Schott
4. C. Lane
5. D. Holtzman
6. David Watson
7. L. Mucke
8. G. Bu

Citations in the corpus

• The amyloid hypothesis of Alzheimer's disease at 25 years (2016, background): “Progressive cleavages of the APP transmembrane domain by the Presenilin/c-secretase complex. innate immune system; and endosomal vesicle recycling (Jones et al, 2010).”
• Alzheimer's disease (2018, background): “A number of AD-risk genes, including CR1, CD33 and TREM2, are involved in immune system pathways [36,37].”