Patients with low serum cobalamin levels and no obvious evidence of deficiency are generally thought to have falsely low levels. However, subtle metabolic deficiency can be detected in most such cases with the deoxyuridine suppression test. Moreover, many also display subtle malabsorption; while absorbing free cobalamin adequately, they malabsorb protein-bound cobalamin. With these new insights, we now propose to re-examine the issue of frequently low cobalamin levels in patients with dementia. We will test patients with Alzheimer's disease and other dementias, identify those with low levels, study them for subtle deficiency states, examine the causes, and determine the effect of therapy. We will apply for the first time to such a project the newer, more sophisticated techniques (deoxyuridine suppression, egg-cobalamin absorption tests, evoked potential studies, EEG with compressed spectral array, cobalamin kinetic studies), careful tests of mental status, and appropriate controls. This should provide answers to the often debated questions concerning the role of cobalamin deficiency in dementia. We will also screen relatives to determine if familial incidence is increased and to address the possibility that preventive measures may be warranted. The second area of our proposal concerns the mechanisms whereby the relatively common entity of subtle cobalamin deficiency arises. The nature of protein-bound cobalamin malabsorption is unclear. We will explore whether non-gastric defects, such as clinically inapparent bacterial overgrowth in the gut, salivary abnormalities, or other intestinal defects, contribute to it. In vivo and in vitro modifications of the egg-cobalamin test, tests for bacterial overgrowth and tests of absorption, as well as more detailed study of gastric function will be used. Since still other patients with subtle deficiency have had no evident malabsorption at all, we will examine kinetics and distribution of cobalamin in vivo and cell uptake in vitro, and assess dietary intake. These studies of subtle malabsorptive processes and possibly new entities of non- gastrointestinal causes of deficiency should clarify several poorly understood aspects of cobalamin absorption, transport and metabolism.