This application is a request for an ADAMHA RSDA (Level II) to support the candidate's continued professional development. During the award period of his RSDA (Level I), the candidate characterized a cell membrane correlate of a subgroup of patients who suffer from Alzheimer's disease (AD). Increased platelet membrane fluidity, as determined by the steady-state fluorescence anisotropy of diphenylhexatriene in labeled membranes, identifies a subgroup of demented patients who have distinct clinical features, including an earlier age at onset, more rapid cognitive decline, and fewer risk factors for ischemic brain. Furthermore, this platelet membrane variant is stable over time, is vertically transmitted in families and expressed in asymptomatic relatives,and predicts the age at onset of dementia among first-degree relatives of probands with AD. A segregation analysis of nuclear families revealed that at least 80% of the observed variance in platelet membrane fluidity could be accounted for by the segregation of a single major locus, PM. Additional evidence suggests that this locus may reside on the long arm of chromosome 21, where other genes relevant to the biology of AD have been localized. The Research Plan focuses in detail on a proposed linkage study of the EM locus, initially with RFLPs on chromosome 21, with the goals of confirming the existence of the PMF locus and determining its location in the human genome. These represent the next steps toward the future goal of cloning the locus, toward a better understanding of its role in the molecular pathology of AD. Together with ongoing clinico-pathologic studies of brain morphologic/neurochemical correlates of behavioral syndromes (depression, psychosis) that emerge in the context of AD, these two experimental strategies comprise the candidate's research program whose focus is the study of determinants of clinical heterogeneity in AD.