Alzheimer's Disease Research - Completed Award
Alison Goate, D.Phil.
St. Louis, MO
Title: Identification of functional alleles that influence cerebrospinal fluid levels of Aß and risk for Alzheimer's disease
Non-Technical Title: Searching for genetic variation that influences cerebrospinal fluid protein levels and risk for Alzheimer's disease
Duration: April 1, 2008 - March 31, 2012
Award Type: Standard
Award Amount: $400,000
Comparisons of levels of A Beta peptides found in the cerebrospinal fluid can be used to predict the risk of developing Alzheimer's disease. By searching for genes that perturb the ratios of ABeta levels in the CSF this proposal seeks to identify new genes involved in the development of late onset Alzheimer's disease.
My proposal has been designed to identify novel genes and pathways that influence a person's risk for developing Alzheimer's disease (AD). I am taking a unique approach to this question by using cerebrospinal fluid protein levels that are known to correlate with whether someone has AD or not in a genetic study. This approach provides a specific biological mechanism for the effect of the genetic variation on AD, making subsequent experiments to identify the function of the genetic variation simple and straightforward. I will first follow-up my previous findings in independent samples to prioritize genes for further study. Second, I will study the high priority genes in depth, identifying the variation responsible for the effects on AD. Third, I will characterize the biological mechanism by which the variation causes these effects. The successful identification and characterization of genetic variation that affects risk for AD will help us learn about why people develop AD, thus providing new targets for AD drug treatment.
Kauwe JS, Bertelsen S, Mayo K, Cruchaga C, Abraham R, Hollingworth P, Harold D, Owen MJ, Williams J, Lovestone S, Morris JC, Goate AM; Alzheimer's Disease Neuroimaging Initiative. Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):955-9.
Kauwe JS, Wang J, Mayo K, Morris JC, Fagan AM, Holtzman DM, Goate AM. Alzheimer's disease risk variants show association with cerebrospinal fluid amyloid beta. Neurogenetics. 2009 Feb;10(1):13-7. Epub 2008 Sep 24.
We have attempted to identify genes that influence variation in cerebrospinal fluid (CSF) levels of beta-amyloid. We anticipate that some of these genes will also influence risk for Alzheimer’s disease (AD), because the presence of beta-amyloid in spinal fluid is associated with the presence of plaques in the brain - hallmarks of AD. In our initial studies, we have identified a polymorphism (a change in the “spelling” of a gene’s sequence) in the Transferrin gene that causes a change in the resulting protein. This change is associated with a higher risk for AD and with higher levels of Aß42 in the CSF. Aß42 peptide is a key toxic component in the initiation of the AD pathology. We also sequenced the Transferrin gene in individuals with very high and very low Aß42 peptide levels and identified a second change in two individuals with high Aß42 levels. When we introduced the normal (non-changed) Transferrin gene into cultured human cells, we found that it lowered total Aß levels. When the mutant gene was introduced into the same cells, it also lowered total Aß Levels, but increased the ratio of Aß42/Aß40 peptides in a manner similar to mutations that cause early onset forms of Alzheimer’s disease.