Identification of functional alleles that influence cerebrospinal fluid levels of Aß and risk for Alzheimer's disease

Progress Updates

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.