I am interested in clinical and basic research on Alzheimer's disease (AD) and other neurodegenerative disorders. In particular, I have focused on biological markers and genes related to AD, and understanding the clinical course and ways to intervene in AD.
Cerebrospinal (CSF) Fluid Markers. Together with collaborators, I have found that levels of the proteins tau and beta-amyloid protein may be useful markers for AD. Using sensitive tests to measure these in CSF, we have found that tau is increased in many patients with Alzheimer's, and a form of beta protein called Ab42 is decreased in many Alzheimer patients. These markers may be useful in identifying AD, even in very early stages. In characterizing tau protein in CSF, we have found that it is cleaved, indicating protease activity. This protease activity may be a factor in AD or neuronal death and is being studied and characterized.
Subtypes of Alzheimer's Disease. My colleagues and I have identified the Lewy body variant of AD as accounting for about 15 percent of patients at our center, many of whom were originally thought to have AD. Lewy bodies in this disorder are found in a variety of brain areas. We have identified a clinical profile to help to diagnose this disorder, that includes hallucinations, parkinsonism, and a subcortical profile of cognitive deficits as being useful in the early diagnosis. We have also found that the density of Lewy bodies in the brain correlates with the severity of cognition measured close to the time of death. These studies show that Lewy bodies can contribute to dementia. Biological markers and genetic risk factors for Lewy body dementia are currently being sought.
Genetic Risk Factors for AD. We have studied phenotypic aspects of apolipoprotein E, of which the e4 allele is a risk factor for AD. We have shown that patients who have the e4 allele have an excess of amyloid deposition in their brains in the form of senile plaques, and also an excess number of neuritic plaques. We have recently identified a family with very early onset of AD who have novel mutation in the gene for the protein presenilin 1 on chromosome 14, which is linked to onset of AD in their mid-30s. The search for further genes relevant to AD and other dementias continues.
Galasko, D., Corey-Bloom, J., and Thal, L.J. (1991). Monitoring progression in Alzheimer's disease. J. Am. Geriatr. Soc. 39: 932-941.
Seubert, P., Oltersdorf, T., Lee, M.G., Galasko, D., et al. (1993). Secretion of B-amyloid precursor protein cleaved at the amino terminus of the B-amyloid peptide. Nature 361: 260-262.
Galasko, D., Hansen, L.A., Katzman, R., et al. (1994). Clinical neuropathological correlations in Alzheimer's disease and related dementias. Arch. Neurol. 51: 888-895.
Bondi, M.W., Monsch, A.U., Galasko, D., Butters, N., Salmon, D.P., and Delis, D.C. (1994). Preclinical cognitive markers of dementia of the Alzheimer type. Neuropsychology 8: 374-384.
Galasko, D., Saitoh, T., Xia, Y. et al. (1994). The Apolipoprotein E allele e4 is over-represented in patients with the Lewy body variant of Alzheimer's disease. Neurology 44: 1950-1951.
Motter, R., Vigo-Pelfrey, C., Kholodenko, D., Barbour, R., Johnson-Wood, K., Galasko, D., et al. (1995). Reduction of amyloid beta peptide42 in the CSF of patients with Alzheimer's disease. Ann. Neurol. 38: 643-648.
McKeith, I.G., Galasko, D., Wilcock, G.K., Byrne, E.J. (1995). Lewy body dementia: diagnosis and treatment. Br. J. Psychiatry 167: 709-717.
Galasko, D., Clark, C., Chang, L., Miller, B. et al. Assessment of cerebrospinal fluid levels of tau protein in mildly demented patients with Alzheimer's disease. Neurology, in press.