SEARCH FOR NEW GENES CAUSING DEMENTIA: TARGETS FOR NOVEL DIAGNOSTICS AND THERAPEUTICS

To date four genes causing Familial Alzheimer’s Disease (FAD) and one gene causing Fronto-Temporal Dementia (FTD) have been identified. These genes provide a partial picture of the biochemical changes causing these diseases, confirming the importance of events that lead to the accumulation of neurotoxic amyloid beta-peptide (Abeta) (as amyloid plaques) and tau proteins (as neurofibrillary tangles). Some of these genes and their protein products have recently been used as the basis for still rather imperfect tests for AD (e.g. CSF Abeta and tau), and as the basis for the development of potential therapies (e.g. gamma-secretase inhibitors which bind to presenilin 1, an FAD gene, and inhibit Abeta production). However, there are numerous gaps in our knowledge of the biochemistry of these diseases (eg. how does Abeta cause neurofibrillary tangles; once initiated by Abeta, can neurofibrillary tangles continue to injure neurons independently of Abeta?). It is unclear whether new “candidate therapies” directed purely at Abeta will be effective by themselves. Furthermore, some of these therapies (eg. gamma-secretase inhibitors) will have significant toxicity because of their mechanism-based effects on the normal processing of other proteins. The current proposal to discover new genes will have three effects. First, these genes can be used to identify individuals at risk for these diseases (who can then be treated before irreversible damage is done). Second, these genes can be used to identify the downstream biochemical processes, which they activate. Finally, the proteins produced by these genes can be directly used as molecular targets for rational drug development.