BIOLOGICAL MARKERS FOR CLINICAL HETEROGENEITY IN AD

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This is a request for a Scientist Development Award (K21). The candidate proposes to obtain additional training in molecular neuroscience, and the correlation of genetic and molecular data with clinical presentation in Alzheimer's disease (AD). The career development plan involves increasing the candidate's conceptual knowledge of molecular neuroscience and clinical correlation. Further, the candidate will enhance or acquire technical skills in quantification of mRNA, cell surface protein detection, radioimmunoassay (RIA), metabolic labeling and immunoprecipitation of proteins, and molecular genetics. Skills in statistical analysis, particularly those relating to correlation of biological genetic, and clinical data, will also be enhanced. The research plan focuses on biological markers for clinical heterogeneity in AD. Apolipoprotein E (Apo E) and the beta-amyloid peptide (betaAP) are currently the best candidates for biological markers for Alzheimer's disease (AD). Most studies, however, have focused on the use of these markes in diagnosis. Few have addressed whether Apo E genotype and/or beta-amyloid expression represent dimensions of biological heterogeneity which correlate with clinical heterogeneity in AD. Patients with AD vary significantly along a number of clinical dimensions, yet there is no satisfactory biological explanation for this variation. Our central hypothesis is that Apo E genotype, cerebrospinal fluid (CSF) betaAP, and amyloid protein expression by leukocytes are correlated with clinical severity and rate of decline in AD. CSF betaAP will be determined with a RIA which discriminates among various betaAP species, some of which may be more pathogenic that others. Leukocyte amyloid expression will be measured with reverse transcription and polymerase chain reaction, and fluorescence activated cell sorting. A variety of neuropsychological, clinical, and brain imaging measures will be employed. It is hypothesized that subjects with the Apo epsilon4 allele will be predisposed to rapid clinical decline. Decreased total CSF betaAP and an increase in the expression of Kunitz protease inhibitor (KPI)- containing forms of beta-amyloid precursor protein (betaAPP) by leukocytes should also be associated with rapid decline. Rates of change will be determined from the amyloid measures, which should correlate with rates of clinical decline. Because there is good evidence that Apo E and betaAP interact in the pathophysiology of AD, subjects with the Apo epsilon4 allele should show larger decreases in CSF betaAP levels than do other SAD subjects. The combination of epsilon 4/epsilon4 genotype and markedly abnormal amyloid expression should characterize the most severely impaired subjects. Finally, quantification of CSF betaAP in AD subjects and controls will provide novel data on the contribution of the various betaAP species to the total CSF betaAP pool, which may give new insight into the basic biological processes by which betaAP is generated. Likewise, leukocyte data will be valuable in clarifying the processing of betaAPP by this important population of cells.