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Genome-Wide Association Studies of Alzheimer?s Disease

Alzheimer?s disease is the most common cause of loss of memory and cognitive abilities in late life, and is currently estimated to affect more than five million Americans. That number is projected to more than double by 2050 unless a way to delay or prevent its onset can be identified. About 50% of individuals with Alzheimer?s disease also experience psychotic symptoms, delusions and hallucinations, which cause additional distress for patients and their family caregivers. Unfortunately, psychotic symptoms are not treated very effectively by available medications, all of which were initially developed for use in individuals with other illnesses.

One approach to find new ways to delay Alzheimer?s disease, or find more effective treatments for the psychotic symptoms, is to identify variations in genes that may affect the age of onset of the illness or that may increase the risk that psychotic symptoms occur. Until recently, only the apolipoproteinE gene had been identified as lowering age of onset in Alzheimer?s disease, and no genes had been clearly linked to the psychotic symptoms. Efforts to identify genes for a number of conditions, however, have benefitted greatly from a new method, Genome-Wide Association (GWA), which can simultaneously evaluate several million genetic variations. 

In these two related papers, Dr. Sweet and collaborators used GWA in an effort to discover additional genes influencing the age of onset of Alzheimer?s disease and the risk for psychotic symptoms. In the paper by Kamboh et al., 11 genetic variations potentially impacting the age of onset of Alzheimer?s disease were newly identified. In the paper by Hollingworth et al., 18 genetic variations were newly identified as potentially associated with the risk of psychosis in Alzheimer?s disease. Of interest, two of these genes, VSNL1 and STK11, have been previously tied to psychosis in schizophrenia and to Alzheimer?s disease itself, indicating they are plausible biologic targets for future studies.

Contributors for article entitled Genome-wide association analysis of age-at-onset in Alzheimer?s disease:
MI Kamboh, MM Barmada, FY Demirci, RL Minster, E Feingold (Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA)MM Carrasquillo, VS Pankratz, SG Younkin (Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL)
AJ Saykin (3Departments of Radiology and Imaging Sciences and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN)
RA Sweet
ST DeKosky (Office of the Dean and Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA)
OL Lopez (Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA)

The results of this investigation were published in the December 2012 issue of Molecular Psychiatry. Click here for a link to the abstract.

Contributors for the article entitled Genome-wide association study of Alzheimer?s disease with psychotic symptoms:
P Hollingworth, R Sims, D Harold, G Russo, R Abraham, A Stretton, N Jones, A Gerrish, J Chapman, D Ivanov, V Moskvina, P Holmans, L Jones, MJ Owen, MC O?Donovan, J Williams (Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK)
R Sweet, B Devlin, L Klei (Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA)
S Lovestone, P Priotsi, M Lupton (Kings College London, Department of Neuroscience, Institute of Psychiatry, London, UK)
C Brayne (Kings College London, Department of Neuroscience, Institute of Psychiatry, London, UK)
M Gill, B Lawlor, A Lynch (Mercer?s Institute for Research on Aging, St James Hospital and Trinity College, Dublin, Ireland)
D Craig, B McGuinness, J Johnston, P Passmore (Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen?s University of Belfast, Belfast, UK)
C Holmes (Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK)
G Livingston, NJ Bass, H Gurling, A McQuillin (Department of Mental Health Sciences, University College London, London, UK)
MM Barmada, FY Demirci (Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA)
ST DeKosky, OL Lopez (3Department of Neurology, University of Pittsburgh, School of Medicine, Pittsburgh, PA)
R Mayeux (Taub Institute and the Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY)
MI Kamboh (Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA)

The results of this investigation were published in the December 2012 issue of Molecular Psychiatry. Click here for a link to the abstract.