Persons with Down syndrome (DS) (40 years and older), who have come to autopsy show brain lesions similar to those seen in patients with Alzheimer disease (AD). It has also been noted that DS persons have abnormal humoral and cell-mediated immune responses. Little is known regarding the relationship between the immune responses, and the presence of AD neuropathology in DS. However, recent studies have suggested that microglia and inflammatory cytokines participate in the pathogenesis of AD. The overall goal of this project is to increase our understanding of the potential role of the cytokines in the pathogenesis of AD, and its relationship to dementia of the Alzheimer type (DAT) in DS. Preliminary studies of 41 aging persons with DS showed that: 1. interleukin-6 (IL- 6), one of the cytokines with immunoregulatory effects, was significantly increased compared to gender- and age-matched normal controls; and 2. Il- 6 levels were significantly higher in the early stage of DAT compared to those without evidence of DAT. Three hypotheses will be tested: 1. Cytokine abnormalities will precede the appearance of signs of DAT, 2. cytokine abnormalities will be greatest in DA showing the most advanced stages of DAT, and 3. cytokine levels in serum will correlate with those of brain and cerebrospinal fluid (CSF) in DS persons. The goal of the proposed investigation is to examine the levels of IL-6 and related cytokines in blood collected annually over a period of five years to observe sequential and progressive changes. Levels of IL-6, IL-1, tumor necrosis factor alpha, and interferon gamma in serum will be measured from 100 persons with DS (41 years and up), using an ELISA. Similar assays will be performed in sera from equal numbers of gender-and age- matched normal controls to rule out effects of age-associated phenomena in cytokine activation. The data will be correlated with clinical evidence of DAT examined annually using logistical regression analysis methods. The results may lead to the development of a laboratory test to predict early signs of AD before the onset of DAT, and offer a method to monitor changes in the severity of DAT. CSF and serum cytokine levels, and the cellular immune response in blood leukocytes will be examined in a subgroup of DS persons; cytokine messenger RNA expression in DS and control brains will be measured by reverse transcriptase- polymerase chain reaction. The studies will determine the relationship of cytokine production in brain and blood in response to DAT in DS.